Switch receptors using il-9 signaling domains

ABSTRACT

The present disclosure generally relates to, inter alia, a class of chimeric switch receptors containing an endodomain of an IL-9 receptor, engineered to modulate transcriptional regulation in a ligand-dependent manner. The disclosure also provides compositions and methods useful for producing such receptors, nucleic acids encoding same, host cells genetically modified with the nucleic acids, as well as methods for modulating gene expression, modulating an activity of a cell, and/or for the treatment of various health conditions or diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 63/245,661, filed Sep. 17, 2021, which is incorporatedherein by reference in its entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with Government support under Contract AI051321awarded by the National Institutes of Health. The Government has certainrights in the invention.

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

The contents of the electronic sequence listing 051288-502001US.xml;Size: 348 Kb; and Date of Creation: Dec. 4, 2022 is hereby incorporatedby reference in its entirety.

FIELD

The present disclosure relates generally to synthetic cellular receptorsthat bind extracellular ligands and have IL-9 endodomains. Thedisclosure also provides compositions and methods useful for producingsuch receptors, nucleic acids encoding same, host cells geneticallymodified with the nucleic acids, as well as methods for modulating geneexpression, modulating an activity of a cell, and/or for the treatmentof various health conditions or diseases.

BACKGROUND

The manipulation of cells, particularly immune cells, to differentiate,develop specialized functions and expand in numbers is of great clinicalinterest. Many protein factors that affect these activities are known inthe art, including in particular cytokines and chemokines. However,these signaling molecules also have pleiotropic effects on cells nottargeted for manipulation, and thus methods of selectively activatingsignaling in a targeted cell population are desirable. The ability toengineer immune cells to carry out controlled behaviors is of interestin the field. For example, in adoptive immunotherapy T cells areisolated from blood, processed ex vivo, and re-infused into patients.Such T cells have been developed for use in therapeutic applicationssuch as the treatment of cancer, infection, and autoimmune diseases.

A critical challenge in cell based therapies is the ability to engineerreceptors that respond to native molecules while also allowing theselective manipulation of immune cells. Some groups have manipulatedproteins to bind and respond to modified ligands in a mannerindependent, or orthogonal, from the influence of the native proteins orligands. This technology relies on the engineering of both an orthogonalcytokine and an orthogonal receptor, and, relies on the premise thatnative molecules will not recognize the orthogonal receptor. One of thechallenges associated with generating orthogonal ligand-receptor pairsis finding mutations that efficiently prevent activation by theendogenous molecule without otherwise compromising the receptor'sstructure or intrinsic ability to activate gene transcription. Inalternative methods, to modulate signaling in immune cells, the onlyapproach to prevent negative signals delivered by molecules such asPD-1, is to give patients systemic treatment of antagonistic antibodiesthat bind to PD-1. This approach has the limitation that systemictreatment prevents T cells that are present in the tumormicroenvironment and the entire immune system from being inactivated,which in some patients can result in autoimmunity or systemicinflammatory syndrome (Beck et al., 2006, J Clin Oncol 24: 2283-9;Blansfield et al., 2005, J Immunother 28: 593-8; Dougan et al., 2009,Annual Review of Immunology 27: 83-117).

The disclosure provided here provides solutions to the problems existingwith previous attempts to manipulate immune cells and potentially offerimproved methods for treatments involving cell transfer.

SUMMARY

The present disclosure generally relates to, among other things,chimeric switch receptors containing an endodomain of an IL-9 receptor,engineered to modulate transcriptional regulation in a ligand-dependentmanner. The activity of these switch receptors can be controlled by thepresence of an extracellular ligand, allowing for spatial and temporalcontrol of specific gene expression in mammalian cells, as well as foruse in modulating cell activities or in treating various healthconditions, such as diseases.

In one aspect, provided herein are recombinant nucleic acid moleculesencoding chimeric receptors that comprise an extracellular portioncomprising a binding domain of an endogenous cytokine receptor, anintracellular portion comprising an endodomain of an IL-9 receptor, anda transmembrane domain that joins the extracellular portion andintracellular portion.

In some embodiments, the recombinant nucleic acid molecule furthercomprises one or more linkers.

In some embodiments, the endogenous cytokine receptor is selected fromIL-2rb, IL-2ra, IL-4r, IL-7ra, IL-15ra, and IL-21ra.

In some embodiments, the endogenous cytokine receptor comprises an aminoacid sequence having at least 80% sequence identity to an amino acidsequence selected from SEQ ID Nos: 1-6.

In some embodiments, the transmembrane domain is selected from thetransmembrane domain of IL-9, IL-7ra, IL-2rb, and TNFR1. In someembodiments, the transmembrane domain comprises an amino acid sequenceselected from SEQ ID Nos: 53-56.

In some embodiments, the chimeric receptor comprises an amino acidsequence having at least 80% sequence identity to an amino acid sequenceselected from SEQ ID Nos: 63-80.

Another aspect provides recombinant nucleic acid molecules encodingchimeric receptors comprising an extracellular portion comprising abinding domain of an endogenous inhibitory receptor an intracellularportion comprising an endodomain of an IL-9 receptor linked to a BOX1/2common gamma chain domain; and a transmembrane domain that joins theextracellular portion and the intracellular portion.

In some embodiments, the recombinant nucleic acid molecule furthercomprises one or more linkers.

In some embodiments, the endogenous inhibitory receptor is selected fromTGF-beta R1, TGF-beta R2, IL-10ra, FAS, CTLA4, LAG3, TIM3, PD1, ILT2,ILT3, ILT4, ILT5, and VEGF.

In some embodiments, the endogenous inhibitory receptor comprises anamino acid sequence having at least 80% sequence identity to an aminoacid sequence selected from SEQ ID Nos: 7-52.

In some embodiments, the transmembrane domain is selected from thetransmembrane domain of IL-9, IL-7ra, IL-2rb, and TNFR1.

In some embodiments, the transmembrane domain is selected from thetransmembrane domain of IL-9, IL-7ra, IL-2rb, and TNFR1.

In some embodiments, the chimeric receptor comprises an amino acidsequence having at least 80% sequence identity to an amino acid sequenceselected from SEQ ID Nos: 81-203.

Another aspect provides recombinant nucleic acid molecules encodingchimeric receptors comprising an extracellular portion comprising abinding domain of an endogenous inhibitory receptor linked to an agentspecific for the common gamma chain; an intracellular portion comprisingan endodomain of an IL-9 receptor; and a transmembrane domain that joinsthe extracellular portion and the intracellular portion.

In some embodiments, the recombinant nucleic acid molecule furthercomprises one or more linkers.

In some embodiments, the endogenous inhibitory receptor is selected fromTGF-beta R1, TGF-beta R2, IL-10ra, FAS, CTLA4, LAG3, TIM3, PD1, ILT2,ILT3, ILT4, ILT5, and VEGF.

In some embodiments, the endogenous inhibitory receptor comprises anamino acid sequence having at least 80% sequence identity to an aminoacid sequence selected from SEQ ID Nos: 7-52.

In some embodiments, the transmembrane domain is selected from thetransmembrane domain of IL-9, IL-7ra, IL-2rb, and TNFR1. In someembodiments, the transmembrane domain comprises an amino acid sequenceselected from SEQ ID Nos: 53-56.

In some embodiments, the agent specific for the common gamma chaincomprises a nanobody, a darpin, IL-2, IL-4, IL-7, and scFV.

Another aspect relates to an expression vector comprising therecombinant nucleic acid molecules of the disclosure.

Another aspect relates to a host cell comprising the expression vectorof the present disclosure. In some embodiments, the host cell is amammalian cell. In some embodiments, the host cell is an immune cell.

Another aspect provides a composition comprising a recombinant nucleicacid of the present disclosure.

Another aspect provides a composition of cells comprising the expressionvector of the present disclosure.

Another aspect provides a polypeptide encoded by the recombinant nucleicacid the present disclosure.

Another aspect provides a composition of one or more polypeptidesencoded by one or more recombinant nucleic acids of the presentdisclosure.

Another aspect provides a composition of cells capable of expressing thechimeric receptor encoded by the recombinant nucleic acid of the presentdisclosure.

Another aspect provides a composition of cells comprising a chimericreceptor comprising an amino acid sequence selected from SEQ ID Nos:63-203.

Another aspect relates to a method for modulating the activity of animmune cell comprising administering, to an immune cell, the recombinantnucleic acid of the present disclosure.

Another aspect relates to a method of treating a subject that involvesadministering, to the subject, a cell expressing the recombinant nucleicacid of the present disclosure.

In some embodiments, the subject is treated for cancer.

In some embodiments, the subject is treated for autoimmune disease.

In some embodiments, the subject is treated for infection.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative embodiments andfeatures described herein, further aspects, embodiments, objects andfeatures of the disclosure will become fully apparent from the drawingsand the detailed description and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the pSTAT expression profile in either stimulated orunstimulated primary human T cells transduced with a lentiviral vectorencoding switch receptors of SEQ ID NO:63+CAR+(IL21R ECD+IL9R TM+IL9RICD and CAR 4D5), SEQ ID NO:66 (IL15Ra+IL9R TM+IL9R ICD), SEQ IDNO:72+CAR+(IL4R ECD+IL9R TM+IL9R ICD and CAR 4D5), or SEQ IDNO:153+CAR+(IL10Ra ECD+IL9R TM+IL9R ICD and CAR 4D5).

FIG. 2 shows a real-time cytotoxicity assay (RTCA) with T cellsco-expressing switch receptor SEQ63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) against SKOV-3 human ovarian adenocarcinoma cells expressing HER2.Double-positive T cells (SEQ63+CAR+) were left unstimulated (“no stim”)before being added on SKOV-3 tumor cells at a 1:8 effector-to-targetratio, or preconditioned for 48 hours with IL21 before addition to theplate with continued ligand stimulation (“preconditioned+IL21”).Untransduced T cells (UTD) served as control and were added on tumorcells with continued IL21 stimulation (“UTD+IL21”).

FIG. 3 shows a real-time cytotoxicity assay (RTCA) with T cellsco-expressing switch receptor SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR(4D5) against SKOV-3 human ovarian adenocarcinoma cells expressing HER2.Double-positive T cells (SEQ72+CAR+) were left unstimulated (“no stim”)before being added on SKOV-3 tumor cells at a 1:8 effector-to-targetratio, or preconditioned for 48 hours with IL4 before addition to theplate with continued ligand stimulation (“preconditioned+IL4”).Untransduced T cells (UTD) served as control and were added on tumorcells with continued IL4 stimulation (“UTD+IL4”).

FIG. 4 shows a real-time cytotoxicity assay (RTCA) with T cellsco-expressing switch receptor SEQ113 (Fas ECD+IL9R TM+IL9R ICD) and CAR(4D5) against SKOV-3 human ovarian adenocarcinoma cells expressing HER2.Double-positive T cells (SEQ113+CAR+) were left unstimulated (“no stim”)before being added on SKOV-3 tumor cells at a 1:4 effector-to-targetratio, or preconditioned for 48 hours with FasL before addition to theplate (“preconditioned+no stim”). Untransduced T cells (UTD) served ascontrol and were added on tumor cells unstimulated (“UTD+no stim”).

FIG. 5 shows hybrid cytokine receptors induce functional activation of Tcells in response to ligand stimulation. T cells were transduced withhybrid cytokine receptor SEQ63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) and cocultured with IL-21 (i) before, (ii) during, or (iii)before+during, co-culture with target cells for 160 hrs. Cell culturesupernatants were collected and the concentrations of effector cytokinesmeasured by Luminex assay. The graph depicts fold change overunstimulated.

FIG. 6 shows hybrid cytokine receptors induce functional activation of Tcells in response to ligand stimulation. T cells were transduced withhybrid cytokine receptor SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR (4D5)and cocultured with IL-4 (i) before, (ii) during, or (iii)before+during, co-culture with target cells for 160 hrs. Cell culturesupernatants were collected and the concentrations of effector cytokinesmeasured by Luminex assay. The graph depicts fold change overunstimulated.

FIG. 7 shows hybrid cytokine receptors induce functional activation of Tcells in response to ligand stimulation. T cells were transduced withhybrid cytokine receptor SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR (4D5)and cocultured with IL-4 (i) before, (ii) during, or (iii)before+during, co-culture with target cells for 160 hrs. Cell culturesupernatants were collected and the concentrations of effector cytokinesmeasured by Luminex assay. The graphs shows concentration of EGF inpg/mL.

FIGS. 8A-8B show hybrid cytokine receptors induce functional activationof T cells in response to ligand stimulation. T cells were transducedwith hybrid cytokine receptors SEQ63 (IL21R ECD+IL9R TM+IL9R ICD) andCAR (4D5) (FIG. 8A) and SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR (4D5)(FIG. 8B) and cocultured with their respective ligands (i) before, (ii)during, or (iii) before+during, co-culture with target cells for 160hrs. Cell culture supernatants were collected and the concentrations ofeffector cytokines measured by Luminex assay. The graphs showsconcentration of FGF-2 in pg/mL.

FIGS. 9A-9B show hybrid cytokine receptors induce functional activationof T cells in response to ligand stimulation. T cells were transducedwith hybrid cytokine receptors SEQ63 (IL21R ECD+IL9R TM+IL9R ICD) andCAR (4D5) (FIG. 9A) and SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR (4D5)(FIG. 9B) and cocultured with their respective ligands (i) before, (ii)during, or (iii) before+during, co-culture with target cells for 160hrs. Cell culture supernatants were collected and the concentrations ofeffector cytokines measured by Luminex assay. The graphs showsconcentration of GM-CSF in pg/mL.

FIG. 10 shows hybrid cytokine receptors induce functional activation ofT cells in response to ligand stimulation. T cells were transduced withhybrid cytokine receptor SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR (4D5)and cocultured with its respective ligand (i) before, (ii) during, or(iii) before+during, co-culture with target cells for 160 hrs. Cellculture supernatants were collected and the concentrations of effectorcytokines measured by Luminex assay. The graphs shows concentration ofIFNa2 in pg/mL.

FIGS. 11A-11B show hybrid cytokine receptors induce functionalactivation of T cells in response to ligand stimulation. T cells weretransduced with hybrid cytokine receptors SEQ63 (IL21R ECD+IL9R TM+IL9RICD) and CAR (4D5) (FIG. 11A) and SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) andCAR (4D5) (FIG. 11B) and cocultured with their respective ligands (i)before, (ii) during, or (iii) before+during, co-culture with targetcells for 160 hrs. Cell culture supernatants were collected and theconcentrations of effector cytokines measured by Luminex assay. Thegraphs shows concentration of IFNg in pg/mL.

FIG. 12 shows hybrid cytokine receptors induce functional activation ofT cells in response to ligand stimulation. T cells were transduced withhybrid cytokine receptor SEQ63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) and cocultured with its respective ligand (i) before, (ii) during,or (iii) before+during, co-culture with target cells for 160 hrs. Cellculture supernatants were collected and the concentrations of effectorcytokines measured by Luminex assay. The graphs shows concentration ofIL-10 in pg/mL.

FIGS. 13A-13B show hybrid cytokine receptors induce functionalactivation of T cells in response to ligand stimulation. T cells weretransduced with hybrid cytokine receptors SEQ63 (IL21R ECD+IL9R TM+IL9RICD) and CAR (4D5) (FIG. 13A) and SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) andCAR (4D5) (FIG. 13B) and cocultured with their respective ligands (i)before, (ii) during, or (iii) before+during, co-culture with targetcells for 160 hrs. Cell culture supernatants were collected and theconcentrations of effector cytokines measured by Luminex assay. Thegraphs shows concentration of IL-1a in pg/mL.

FIG. 14 shows hybrid cytokine receptors induce functional activation ofT cells in response to ligand stimulation. T cells were transduced withhybrid cytokine receptor SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR (4D5)and cocultured with its respective ligand (i) before, (ii) during, or(iii) before+during, co-culture with target cells for 160 hrs. Cellculture supernatants were collected and the concentrations of effectorcytokines measured by Luminex assay. The graphs shows concentration ofIL-2 in pg/mL.

FIGS. 15A-15B show hybrid cytokine receptors induce functionalactivation of T cells in response to ligand stimulation. T cells weretransduced with hybrid cytokine receptors SEQ63 (IL21R ECD+IL9R TM+IL9RICD) and CAR (4D5) (FIG. 15A) and SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) andCAR (4D5) (FIG. 15B) and cocultured with their respective ligands (i)before, (ii) during, or (iii) before+during, co-culture with targetcells for 160 hrs. Cell culture supernatants were collected and theconcentrations of effector cytokines measured by Luminex assay. Thegraphs shows concentration of IL-3 in pg/mL.

FIGS. 16A-16B show hybrid cytokine receptors induce functionalactivation of T cells in response to ligand stimulation. T cells weretransduced with hybrid cytokine receptors SEQ63 (IL21R ECD+IL9R TM+IL9RICD) and CAR (4D5) (FIG. 16A) and SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) andCAR (4D5) (FIG. 16B) and cocultured with their respective ligands (i)before, (ii) during, or (iii) before+during, co-culture with targetcells for 160 hrs. Cell culture supernatants were collected and theconcentrations of effector cytokines measured by Luminex assay. Thegraphs shows concentration of IL-6 in pg/mL.

FIGS. 17A-17B show hybrid cytokine receptors induce functionalactivation of T cells in response to ligand stimulation. T cells weretransduced with hybrid cytokine receptors SEQ63 (IL21R ECD+IL9R TM+IL9RICD) and CAR (4D5) (FIG. 17A) and SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) andCAR (4D5) (FIG. 17B) and cocultured with their respective ligands (i)before, (ii) during, or (iii) before+during, co-culture with targetcells for 160 hrs. Cell culture supernatants were collected and theconcentrations of effector cytokines measured by Luminex assay. Thegraphs shows concentration of IP-10 in pg/mL.

FIGS. 18A-18B show hybrid cytokine receptors induce functionalactivation of T cells in response to ligand stimulation. T cells weretransduced with hybrid cytokine receptors SEQ63 (IL21R ECD+IL9R TM+IL9RICD) and CAR (4D5) (FIG. 18A) and SEQ72 (IL4R ECD+IL9R TM+IL9R ICD) andCAR (4D5) (FIG. 18B) and cocultured with their respective ligands (i)before, (ii) during, or (iii) before+during, co-culture with targetcells for 160 hrs. Cell culture supernatants were collected and theconcentrations of effector cytokines measured by Luminex assay. Thegraphs shows concentration of MIP-1a in pg/mL.

FIG. 19 shows hybrid cytokine receptors induce functional activation ofT cells in response to ligand stimulation. T cells were transduced withhybrid cytokine receptor SEQ63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) and cocultured with its respective ligand (i) before, (ii) during,or (iii) before+during, co-culture with target cells for 160 hrs. Cellculture supernatants were collected and the concentrations of effectorcytokines measured by Luminex assay. The graphs shows concentration ofRANTES in pg/mL.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure generally relates to, among other things,chimeric switch receptors containing an endodomain of an IL-9 receptorand a binding domain of an endogenous receptor, wherein the chimericswitch receptor is engineered to modulate transcriptional regulation ina ligand-dependent manner. The activity of these switch receptors can becontrolled by the presence of an extracellular ligand, allowing forspatial and temporal control of specific gene expression in mammaliancells, as well as for use in modulating cell activities, immune systemresponses, or in treating various health conditions, such as diseases.Particularly, the chimeric switch receptor (termed “IL-9 switchreceptor”), even though containing the endodomain of an IL-9 receptor,does not require IL-9 for activation and can be tailored to be activatedby ligands specific for the binding domains of the endogenous receptors,such as normally inhibitory ligands. This class of chimeric switchreceptors is synthetic and recombinant, and does not occur in nature. Asdescribed below, the chimeric switch receptors disclosed herein can besynthetic polypeptides, and can be engineered, designed, or modified soas to provide desired and/or improved properties, e.g., modulatingtranscription. The disclosure also provides compositions and methodsuseful for producing such receptors, nucleic acids encoding same, cellsgenetically modified with the nucleic acids, as well as methods formodulating an activity of a cell, modulating immune system, and/or forthe treatment of various diseases.

In the following detailed description, the illustrative alternativesdescribed in the detailed description and claims are not meant to belimiting. Other alternatives may be used and other changes may be madewithout departing from the spirit or scope of the subject matterpresented here. It will be readily understood that the aspects, asgenerally described herein, can be arranged, substituted, combined, anddesigned in a wide variety of different configurations, all of which areexplicitly contemplated and make part of this application.

Definitions

The singular form “a”, “an”, and “the” include plural references unlessthe context clearly dictates otherwise. For example, the term “a cell”includes one or more cells, including mixtures thereof. “A and/or B” isused herein to include all of the following alternatives: “A”, “B”, “Aor B”, and “A and B.”

The terms “administration” and “administering”, as used herein, refer tothe delivery of a composition or formulation as disclosed herein by anadministration route including, but not limited to, intravenous,intra-arterial, intracranial, intramuscular, intraperitoneal,subcutaneous, intramuscular, or combinations thereof. The term includes,but is not limited to, administration by a medical professional andself-administration.

“Cancer” refers to the presence of cells possessing severalcharacteristics typical of cancer-causing cells, such as uncontrolledproliferation, immortality, metastatic potential, rapid growth andproliferation rate, and certain characteristic morphological features.Cancer cells can aggregate into a mass, such as a tumor, or can existalone within a subject. A tumor can be a solid tumor, a soft tissuetumor, or a metastatic lesion. As used herein, the term “cancer” alsoencompasses other types of non-tumor cancers. Non-limiting examplesinclude blood cancers or hematological cancers, such as leukemia. Cancercan include premalignant, as well as malignant cancers.

The terms “cell”, “cell culture”, and “cell line” refer not only to theparticular subject cell or cell line but also to the progeny orpotential progeny of such a cell, cell culture, or cell line, withoutregard to the number of transfers or passages in culture. It should beunderstood that not all progeny are exactly identical to the parentalcell. This is because certain modifications may occur in succeedinggenerations due to either mutations (e.g., deliberate or inadvertentmutations) or environmental influences (e.g., methylation or otherepigenetic modifications), such that progeny may not, in fact, beidentical to the parent cell, but are still included within the scope ofthe term as used herein, so long as the progeny retain the samefunctionality as that of the original cell, cell culture, or cell line.

As used herein “endogenous” refers to any material from or producedinside an organism, cell, tissue or system (e.g., as it would occur innature or naturally produced).

The term “percent identity”, as used herein in the context of two ormore nucleic acids or proteins, refers to two or more sequences orsubsequences that are the same or have a specified percentage ofnucleotides or amino acids that are the same (e.g., about 60% sequenceidentity, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or higher identity over a specified region, when comparedand aligned for maximum correspondence over a comparison window ordesignated region) as measured using a BLAST or BLAST 2.0 sequencecomparison algorithms with default parameters described below, or bymanual alignment and visual inspection. See e.g., the NCBI web site atncbi.nlm.nih.gov/BLAST. Such sequences are then said to be“substantially identical.” This definition also refers to, or may beapplied to, the complement of a sequence. This definition also includessequences that have deletions and/or additions, as well as those thathave substitutions. Sequence identity can be calculated over a regionthat is at least about 20 amino acids or nucleotides in length, or overa region that is 10-100 amino acids or nucleotides in length, or overthe entire length of a given sequence. Sequence identity can becalculated using published techniques and widely available computerprograms, such as the GCS program package (Devereux et al, Nucleic AcidsRes. 12:387, 1984), BLASTP, BLASTN, FASTA (Atschul et al., Mol Biol215:403, 1990). Sequence identity can be measured using sequenceanalysis software such as the Sequence Analysis Software Package of theGenetics Computer Group at the University of Wisconsin BiotechnologyCenter (1710 University Avenue, Madison, Wis. 53705), with the defaultparameters thereof.

As used herein, a “subject” or an “individual” includes animals, such ashuman (e.g., human subject) and non-human animals. In some embodiments,a “subject” or “individual” is a patient under the care of a physician.Thus, the subject can be a human patient or a subject who has, is atrisk of having, or is suspected of having a disease of interest (e.g.,cancer) and/or one or more symptoms of the disease. The subject can alsobe a subject who is diagnosed with a risk of the condition of interestat the time of diagnosis or later. The term “non-human animals” includesall vertebrates, e.g., mammals, e.g., rodents, e.g., mice, non-humanprimates, and other mammals, such as e.g., sheep, dogs, cows, chickens,and non-mammals, such as amphibians, reptiles, etc.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the disclosure, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the disclosure.

All ranges disclosed herein also encompass any and all possiblesub-ranges and combinations of sub-ranges thereof. Any listed range canbe recognized as sufficiently describing and enabling the same rangebeing broken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,and so forth. As will also be understood by one skilled in the art alllanguage such as “up to”, “at least”, “greater than”, “less than”, andthe like include the number recited and refer to ranges which can besubsequently broken down into sub-ranges as discussed above. Finally, aswill be understood by one skilled in the art, a range includes eachindividual member. Thus, for example, a group having 1-3 articles refersto groups having 1, 2, or 3 articles. Similarly, a group having 1-5articles refers to groups having 1, 2, 3, 4, or 5 articles, and soforth.

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate embodiments, may alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the disclosure, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination. All combinations of the embodimentspertaining to the disclosure are specifically embraced by the presentdisclosure and are disclosed herein just as if each and everycombination was individually and explicitly disclosed. In addition, allsub-combinations of the various embodiments and elements thereof arealso specifically embraced by the present disclosure and are disclosedherein just as if each and every such sub-combination was individuallyand explicitly disclosed herein.

IL-9 and Common Gamma Chain Receptors

Interleukin-9 (IL-9) is a member of a group of cytokines referred to asthe common γ chain cytokines. Common γ chain cytokines exert numerousfunctions on immune cell survival, function and proliferation. The γcfamily consists of six members—IL-2, IL-4, IL-7, IL-9, IL-15, andIL-21—which all have unique receptors. Upon receptor ligation, γccytokines through JAK1 and JAK3 activate various developmental pathwaysincluding STAT1, STAT3, STAT5, MAPK, and PI3K/AKT pathways.

An important aspect of γc receptor signaling is positive and negativeregulation of pathways to either enhance or repress signaling. Some ofthe γc cytokines can mediate similar signaling pathways andtranscriptional programs (Kovanen P E, Rosenwald A, Fu J, Hurt E M, LamL T, Giltnane J M, et al. Analysis of Gamma C-Family Cytokine TargetGenes. Identification of Dual-Specificity Phosphatase 5 (DUSP5) as aRegulator of Mitogen-Activated Protein Kinase Activity in Interleukin-2Signaling. J Biol Chem (2003) 278(7):5205-13; Osinalde N, Sanchez-QuilesV, Akimov V, Guerra B, Blagoev B, Kratchmarova I. SimultaneousDissection and Comparison of IL-2 and IL-15 Signaling Pathways by GlobalQuantitative Phosphoproteomics. Proteomics (2015) 15(2-3):520-31),however, physiological differences in cytokine signaling are mediated bycompetition for γc between the different receptors (Gonnord P, AngermannB R, Sadtler K, Gombos E, Chappert P, Meier-Schellersheim M, et al. AHierarchy of Affinities Between Cytokine Receptors and the Common GammaChain Leads to Pathway Cross-Talk. Sci Signal (2018) 11(524)),variability in receptor expression on T cell subsets, a bias forsignaling through different STAT molecules, and differences inactivation of the MAPK and PI3K pathways (Zeng R, Spolski R, Casas E,Zhu W, Levy D E, Leonard W J. The Molecular Basis of IL-21-MediatedProliferation. Blood (2007) 109(10):4135-42; Gadina M, Sudarshan C,Visconti R, Zhou Y J, Gu H, Neel B G, et al. The Docking Molecule Gab2is Induced by Lymphocyte Activation and is Involved in Signaling byInterleukin-2 and Interleukin-15 But Not Other Common Gamma Chain-UsingCytokines. J Biol Chem (2000) 275(35):26959-66).

The IL-9 receptor alpha (IL-9Rα), a member of the type I hematopoietinreceptor superfamily, has high affinity (Kd of approximately 100 pM) forIL-9. This 64-kDa glycoprotein is reported on a variety of hematopoieticcells, particularly T cells. Similar to the other members of the IL-2receptor family, IL-9Rα also forms a heterotypic receptor complex withthe common gamma (γc) chain. In the IL-9R heterocomplex, the IL-9Rαchain is the ligand binding domain and γ chain serves as the signalingsubunit. The IL-9Rα subunit is characterized by four extracellularcysteines and the conserved WSXWS motif, while the intracellular domaincontains a BOX1 consensus sequence and a serine rich region. IL-9Rα isfound in both membrane bound and soluble forms, whereas the γc subunitis observed only in a membrane bound form.

IL-9 binding to IL-9Rα results in the formation the IL-9R heterocomplex.A hallmark of the IL-9R heterocomplex is the absence of anyintracellular enzymatic activity, and, therefore, Janus kinases (JAK)need to mediate the phosphorylation of the receptor (Knoops L., RenauldJ. C. IL-9 and its receptor: From signal transduction to tumorigenesis.Growth Factors. 2004; 22:207-215). Upon IL-9 binding to the receptor, aconformational change occurs in the IL-9R heterocomplex, which allowsJAK molecules to bind to the proline rich BOX1 motif in themembrane-proximal region of IL-9Ra. JAK1 associates with IL-9Ra, whereasJAK3 binds to γc. Phosphorylated JAK1 and JAK3 then mediate thephosphorylation of receptor tyrosine residues. Phosphorylated tyrosineresidues act as docking sites for the downstream Src homology 2 (SH2)domain containing signaling molecules such as Signal Transducer andActivator of Transcription (STAT) transcription factors, insulinreceptor substrate (IRS), and the adaptors of the Mitogen-ActivatedProtein Kinase (MAPK) pathways.

Compositions of the Disclosure

As described in greater detail below, one aspect of the presentdisclosure relates to recombinant nucleic acids encoding chimeric switchreceptors that include an extracellular portion comprising a bindingdomain of an endogenous cytokine receptor or endogenous inhibitoryreceptor, an intracellular portion comprising an endodomain of an IL-9receptor, and transmembrane domain that joins the extracellular portionand the intracellular portion. Such receptors are engineered to modulatetranscriptional regulation in a ligand-dependent manner with variousadvantages including the ability to convert an otherwise negative signalinto a positive signal in the cell. Thus, the present disclosure alsoencompasses switch receptors that are able to switch negative signals topositive signals for enhancement of an immune response. The presentdisclosure also encompasses receptors that are able to bind to anendogenous or exogenously given ligand (e.g. a cytokine) and, regardlessof the cytokine, result in activation of STAT5, for example, via thecommon gamma chain and IL-9 endodomain.

As described in the Examples, certain recombinant nucleic acids encodingchimeric receptors can be tested and validated in T cells. Thesechimeric receptors are expected to show similar performance in mousemodels as well as models in other suitable animals or in vitro systems.The receptors disclosed herein may be engineered into various immunecell types for enhanced discrimination and elimination of tumors, or inrecombinant host cells for control of autoimmunity and infection.Accordingly, recombinant host cells and compositions of cells, such asimmune cells capable of expressing one of more of the chimeric receptorsdisclosed herein, are also within the scope of the disclosure. In someembodiments, a composition of cells expresses the chimeric receptorencoded by the recombinant nucleic acid described herein.

Switch Receptors

The present disclosure is based, inter alia, on recombinant nucleic acidmolecules encoding chimeric receptors which comprise an endodomain of anIL-9 receptor, thus creating chimeric receptors that can respond tovarious extracellular ligands while maintaining the ability to initiateintracellular signaling through the IL-9 receptor endodomain. Immunecells expressing these chimeric receptors may be useful in the contextof modulating immune cell activity. In some embodiments, the ligand canbe added exogenously and not be limited to production within the cell.

As outlined above, some embodiments of the present disclosure relate torecombinant nucleic acid molecules encoding chimeric receptorscontaining the endodomain of an IL-9 receptor. In particular, thechimeric receptors, even though containing an IL-9 endodomain, do notrequire binding of IL-9 for the functioning of the receptors. Generally,the chimeric receptors comprise an extracellular portion, anintracellular portion comprising an endodomain of an IL-9 receptor, anda transmembrane domain that joins the extracellular portion and theintracellular portion. In some embodiments, extracellular portioncomprises a binding domain of an endogenous cytokine receptor. In someembodiments, the extracellular portion comprises a binding domain of anendogenous inhibitory receptor.

In some embodiments, provided herein is a recombinant nucleic acidencoding a chimeric polypeptide including: (a) an extracellular portioncomprising a binding domain of an endogenous cytokine receptor; (b) anintracellular portion comprising an endodomain of an IL-9 receptor; (c)a transmembrane domain that joins the extracellular portion and theintracellular portion.

In some embodiments, provided herein is a recombinant nucleic acidencoding a chimeric polypeptide including: (a) an extracellular portioncomprising a binding domain of an endogenous inhibitory receptor; (b) anintracellular portion comprising an endodomain of an IL-9 receptorlinked to a BOX1/2 common gamma chain domain; (c) a transmembrane domainthat joins the extracellular portion and the intracellular portion.

In some embodiments, provided herein is a recombinant nucleic acidencoding a chimeric polypeptide including: (a) an extracellular portioncomprising a binding domain of an endogenous inhibitory receptor linkedto an agent specific for the common gamma chain; (b) an intracellularportion comprising an endodomain of an IL-9 receptor; (c) atransmembrane domain that joins the extracellular portion and theintracellular portion.

Extracellular Portions

As outlined above, the extracellular portions of the chimeric receptors(e.g., switch receptors) in some embodiments of the disclosure have abinding domain of an endogenous cytokine receptor or an endogenousinhibitory receptor. A binding domain of an endogenous cytokine receptorcan be an extracellular portion of an endogenous cytokine receptor, or afragment or truncation thereof that can bind a cytokine polypeptidesequence. In some embodiments, the endogenous cytokine receptor is amember of the common gamma chain receptor family. Members of the commongamma chain receptor family are known in the art and are discussedsupra. In some embodiments, the endogenous cytokine receptor is selectedfrom IL-2rb, IL-2ra, IL-4r, IL-7ra, IL-15ra, and IL-21ra. As describedsupra, IL-2rb, IL-2ra, IL-4r, IL-7ra, IL-15ra, and IL-21ra are all partof the common gamma chain family. Therefore, these receptors are capableof recruiting the common gamma chain, upon ligand binding, and signalingcan proceed through the IL-9 endodomain.

In one embodiment, the endogenous cytokine receptor comprises the aminoacid sequence of IL-2rb (SEQ ID NO:1) below:

AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWACNLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAPISLQVVHVETHRCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFR TKPAALGKDT

In one embodiment, the endogenous cytokine receptor comprises the aminoacid sequence of IL-2ra (SEQ ID NO:2) below:

ELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYMLCTGNSSHSSWDNQCQCTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCREPPPWENEATERIYHFVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGEEKPQASPEGRPESETSCLVTTTDFQIQTE MAATMETSIFTTEYQ

In one embodiment, the endogenous cytokine receptor comprises the aminoacid sequence of IL-4 (SEQ ID NO:3) below:

MKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRLLYQLVFLLSEAHTCIPENNGGAGCVCHLLMDDVVSADNYTLDLWAGQQLLWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSNPYPPDNYLYNHLTYAVNIWSENDPADFRIYNVTYLEPSLRIAASTLKSGISYRARVRAWAQCYNTTWSEWSPSTKWHNSYREPF EQH

In one embodiment, the endogenous cytokine receptor comprises the aminoacid sequence of IL-7ra (SEQ ID NO:4) below:

ESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDPDVNITNLEFEICGALVEVKCLNFRKLQEIYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSVVYREGANDFVVTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKLQPAAMYEIKVRSIPDHYFKGFWSEWSPSY YFRTPEINNSSGEMD

In one embodiment, the endogenous cytokine receptor comprises the aminoacid sequence of IL-15ra (SEQ ID NO:5) below:

ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQPPGVYPQGHSDTT

In one embodiment, the endogenous cytokine receptor comprises the aminoacid sequence of IL-21ra (SEQ ID NO:6) below:

CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKDEATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIF QTQSEELKE

In some embodiments, the extracellular portions of the chimericpolypeptides disclosed herein (e.g., IL-9 switch receptors) having atleast 80% sequence identity, such as, at least 80%, at least 85%, atleast 90%, at least 95%, at least 96%, at least 97%, at least 98%, or99% sequence identity to a sequence selected from the group consistingof SEQ ID NOS: 1-6 in the Sequence Listing. In some embodiments, theextracellular portion includes an amino acid sequence having at least90% sequence identity to a sequence selected from the group consistingof SEQ ID NOS: 1-6. In some embodiments, the extracellular portionincludes an amino acid sequence having at least 95% sequence identity toa sequence selected from the group consisting of SEQ ID NOS: 1-6. Insome embodiments, the extracellular portion includes an amino acidsequence having about 100% sequence identity to a sequence selected fromthe group consisting of SEQ ID NOS: 1-6. In some embodiments, theextracellular portion includes an amino acid sequence having a sequenceselected from the group consisting of SEQ ID NOS: 1-6, wherein one, two,three, four, or five of the amino acid residues in any one of the SEQ IDNOS: 1-6 is substituted by a different amino acid residue.

In another aspect of the present disclosure, the extracellular portionof the chimeric receptor of the disclosure can also comprise a bindingdomain of an endogenous inhibitory receptor. Specifically, as describedsupra, in some embodiments, provided herein is a recombinant nucleicacid encoding a chimeric polypeptide including: (a) an extracellularportion comprising a binding domain of an endogenous inhibitory receptorlinked to an agent specific for the common gamma chain; (b) anintracellular portion comprising an endodomain of an IL-9 receptor; (c)a transmembrane domain that joins the extracellular portion and theintracellular portion.

As described supra, signaling through the IL-9 endodomain requiresrecruitment of the common gamma chain. In some embodiments, the bindingdomains of the extracellular portion of the inhibitory receptorsdescribed herein are not able to naturally recruit the common gammachain in order to elicit signaling through the IL-9 endodomain of thechimeric receptor. Accordingly, in these embodiments, the binding domainof the endogenous inhibitory receptor is linked to an agent specific forthe common gamma chain. The binding domain of the inhibitory receptor islinked to the agent specific for the common gamma chain such that bothcomponents are able to function in their intended way (e.g., the bindingdomain is able to bind a ligand and the agent specific for the commongamma chain is able to bind the common gamma chain).

In some embodiments, the agent specific for the common gamma chaincomprises agent specific for the common gamma chain comprises ananobody, a darpin, IL-2, IL-4, IL-7, or an scFv.

In some embodiments, an scFv directed to the common gamma chain iscloned in frame with the extracellular portion of the chimeric receptor,with suitable linker sequences inserted between these components. Thebinding of the common gamma chain to the scFv will be sufficient toinduce chimeric receptor dimerization.

scFVs directed to the common gamma chain as well as their sequences areknown in the art and described in WO 2017/021540. However, the use ofscFVs directed to the common gamma chain with respect to switchreceptors is not disclosed therein.

A binding domain of an endogenous inhibitory receptor can be anextracellular portion of an endogenous inhibitory receptor, or afragment or truncation thereof that can bind a cytokine polypeptidesequence and subsequently decrease immune activity. For example, anatural inhibitory receptor can reduce T cell proliferation, T cellsurvival, cytokine release, or immune cell lytic activity upon bindingof a natural agonist.

Endogenous inhibitory receptors are well known in the art and arecontemplated for use in the compositions described herein (Turnis etal., “Inhibitory Receptors as Targets for Cancer Immunotherapy,” Eur JImmunol 2015 45(7):1892-1905).

In some embodiments, the endogenous inhibitory receptor signals throughtrimerization. In some embodiments, the endogenous inhibitory receptoris a member of the TNF receptor superfamily.

In some embodiments, the endogenous inhibitory receptor signals asfunctional dimers of dimers. In some embodiments, the endogenousinhibitory receptor is a member of the TGF beta superfamily ofreceptors. Receptors in this family include, for example, Type I, TypeII, and Type III receptors. Exemplary members of the Type I receptorfamily include, without limitation, ACVRL1, ACVR1A, BMPR1A, ACVR1B,TGFβR1, BMPR1B, and ACVR1C. Exemplary members of the Type II receptorfamily include, without limitation, TGFBR2, BMPR2, ACVR2A, ACVR2B, andAMHR2. TGF βR3 is a member of the Type III family of receptors.

In some embodiments, the endogenous inhibitory receptor signal asdimers. In some embodiments, the endogenous inhibitory receptor is amember of the VEGF family of receptors. Receptors in this familyinclude, for example, VEGFR1, VEGFR2, and VEGFR3.

In some embodiments, the endogenous inhibitory receptor is selected fromTGF-beta R1, TGF-beta R2, IL-10ra, FAS, CTLA4, LAGS, TIM3, PD1, ILT2,ILT3, ILT4, ILT5, and VEGF. Thus, in some embodiments, the extracellularportion of the chimeric receptor of the disclosure can be a bindingdomain of TGF-beta R1, TGF-beta R2, IL-10ra, FAS, CTLA4, LAGS, TIM3,PD1, ILT2, ILT3, ILT4, ILT5, and VEGF.

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of TGFBR1 (SEQ ID NO:7) below:

LQCFCHLCTKDNFTCVTDGLCFVSVTETTDKVIHNSMCIAEIDLIPRDRPFVCAPSSKTGSVTTTYCCNQDHCNKIELPTTVKSSPGLGPVEL

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of TGFBR2 (SEQ ID NO:8) below:

TIPPHVQKSVNNDMTVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQ

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of IL-10ra (SEQ ID NO:9) below:

HGTELPSPPSVWFEAEFFHHILHWTPIPNQSESTCYEVALLRYGIESWNSISNCSQTLSYDLTAVTLDLYHSNGYRARVRAVDGSRHSNWTVTNTRFSVDEVTLTVGSVNLEIHNGFILGKIQLPRPKMAPANDTYESIFSHFREYEIAIRKVPGNFTFTHKKVKHENFSLLTSGEVGEFCVQVKPSVASRSNKGMWSKEECIS LTRQYFTVTN

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of FAS (SEQ ID NO:10) below:

QVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKEEGSRSN

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of CTLA4 (SEQ ID NO:11) below:

KAMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSD

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of LAG3 (SEQ ID NO:12) below:

LQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLRASDWVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWGCILTYRDGFNVSIMYNLTVLGLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGPDLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVTPVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTEL SSPGAQRSGRAPGALPAGHL

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of TIM3 (SEQ ID NO:13) below:

SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANELRDSRLANDLRDSGATIRIG

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of PD1 (SEQ ID NO:14) below:

FTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNHIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEE NHTAELVIPELPLAHPPNER

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of ILT2 (SEQ ID NO:15) below:

GHLPKPTLWAEPGSVITQGSPVTLRCQGGQETQEYRLYREKKTALWITRIPQELVKKGQFPIPSITWEHAGRYRCYYGSDTAGRSESSDPLELVVTGAYIKPTLSAQPSPVVNSGGNVILQCDSQVAFDGFSLCKEGEDEHPQCLNSQPHARGSSRAIFSVGPVSPSRRWWYRCYAYDSNSPYEWSLPSDLLELLVLGVSKKPSLSVQPGPIVAPEETLTLQCGSDAGYNRFVLYKDGERDFLQLAGAQPQAGLSQANFTLGPVSRSYGGQYRCYGAHNLSSEWSAPSDPLDILIAGQFYDRVSLSVQPGPTVASGENVTLLCQSQGWMQTFLLTKEGAADDPWRLRSTYQSQKYQAEFPMGPVTSAHAGTYRCYGSQSSKPYLLTHPSDPLELVVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLGV

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of ILT3 (SEQ ID NO:16) below:

QAGPLPKPTLWAEPGSVISWGNSVTIWCQGTLEAREYRLDKEESPAPWDRQNPLEPKNKARFSIPSMTEDYAGRYRCYYRSPVGWSQPSDPLELVMTGAYSKPTLSALPSPLVTSGKSVTLLCQSRSPMDTFLLIKERAAHPLLHLRSEHGAQQHQAEFPMSPVTSVHGGTYRCFSSHGFSHYLLSHPSDPLELIVSGSLEDPRPSPTRSVSTAAGPEDQPLMPTGSVPHSGLRRHWE

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of ILT4 (SEQ ID NO:17) below:

QTGTIPKPTLWAEPDSVITQGSPVTLSCQGSLEAQEYRLYREKKSASWITRIRPELVKNGQFHIPSITWEHTGRYGCQYYSRARWSELSDPLVLVMTGAYPKPTLSAQPSPVVTSGGRVTLQCESQVAFGGFILCKEGEEEHPQCLNSQPHARGSSRAIFSVGPVSPNRRWSHRCYGYDLNSPYVWSSPSDLLELLVPGVSKKPSLSVQPGPVVAPGESLTLQCVSDVGYDRFVLYKEGERDLRQLPGRQPQAGLSQANFTLGPVSRSYGGQYRCYGAHNLSSECSAPSDPLDILITGQIRGTPFISVQPGPTVASGENVTLLCQSWRQFHTFLLTKAGAADAPLRLRSIHEYPKYQAEFPMSPVTSAHAGTYRCYGSLNSDPYLLSHPSEPLELVVSGPSMGSSPPPTGPISTPAGPEDQPLTPTGSDPQSGLGRHLGV

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of ILT5 (SEQ ID NO:18) below:

GPFPKPTLWAEPGSVISWGSPVTIWCQGSQEAQEYRLHKEGSPEPLDRNNPLEPKNKARFSIPSMTEHHAGRYRCHYYSSAGWSEPSDPLEMVMTGAYSKPTLSALPSPVVASGGNMTLRCGSQKGYHHFVLMKEGEHQLPRTLDSQQLHSRGFQALFPVGPVTPSHRWRFTCYYYYTNTPWVWSHPSDPLEILPSGVSRKPSLLTLQGPVLAPGQSLTLQCGSDVGYNRFVLYKEGERDFLQRPGQQPQAGLSQANFTLGPVSPSNGGQYRCYGAHNLSSEWSAPSDPLNILMAGQIYDTVSLSAQPGPTVASGENVTLLCQSWWQFDTFLLTKEGAAHPPLRLRSMYGAHKYQAEFPMSPVTSAHAGTYRCYGSYSSNPHLLSHPSEPLELVVSGHSG GSSLPPTGPPSTPGLGRYLE

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of VEGFR1 (SEQ ID NO:19) below:

SKLKDPELSLKGTQHIMQAGQTLHLQCRGEAAHKWSLPEMVSKESERLSITKSACGRNGKQFCSTLTLNTAQANHTGFYSCKYLAVPTSKKKETESAIYIFISDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVQISTPRPVKLLRGHTLVLNCTATTPLNTRVQMTWSYPDEKNKRASVRRRIDQSNSHANIFYSVLTIDKMQNKDKGLYTCRVRSGPSFKSVNTSVHIYDKAFITVKHRKQQVLETVAGKRSYRLSMKVKAFPSPEVVWLKDGLPATEKSARYLTRGYSLIIKDVTEEDAGNYTILLSIKQSNVFKNLTATLIVNVKPQIYEKAVSSFPDPALYPLGSRQILTCTAYGIPQPTIKWFWHPCNHNHSEARCDFCSNNEESFILDADSNMGNRIESITQRMAIIEGKNKMASTLVVADSRISGIYICIASNKVGTVGRNISFYITDVPNGFHVNLEKMPTEGEDLKLSCTVNKFLYRDVTWILLRTVNNRTMHYSISKQKMAITKEHSITLNLTIMNVSLQDSGTYACRARNVYTGEEILQKKEITIRDQEAPYLLRNLSDHTVAISSSTTLDCHANGVPEPQITWFKNNHKIQQEPGIILGPGSSTLFIERVTEEDEGVYHCKATNQKGSVESSAYLTVQGTSDKSNLE

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of VEGFR2 (SEQ ID NO:20) below:

ASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLDWLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAVSVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVISFHVTRGPEITLQPDMQPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPTPVCKNLDTLWKLNATMFSNSTNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLTVLERVAPTITGNLENQTTSIGESIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLE

In one embodiment, the endogenous inhibitory receptor comprises theamino acid sequence of VEGFR3 (SEQ ID NO:21) below:

YSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTHTELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTEVIVHENPFISVEWLKGPILEATAGDELVKLPVKLAAYPPPEFQWYKDGKALSGRHSPHALVLKEVTEASTGTYTLALWNSAAGLRRNISLELVVNVPPQIHEKEASSPSIYSRHSRQALTCTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQQDLMPQCRDWRAVTTQDAVNPIESLDTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKVGQDERLIYFYVTTIPDGFTIESKPSEELLEGQPVLLSCQADSYKYEHLRWYRLNLSTLHDAHGNPLLLDCKNVHLFATPLAASLEEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRSHDKHCHKKYLSVQALEAPRLTQNLTDLLVNVSDSLEMQCLVAGAHAPSIVWYKDERLLEEKSGVDLADSNQKLSIQRVREEDAGRYLCSVCNAKGCVNSSASVAVEGSEDKGSM E

A number of other receptor sequences are contemplated for use in theextracellular portions of the chimeric receptors described herein. Suchsequences may be used to switch the natural biology of the receptorligand or provide for localized stimulation of a cell population.Exemplary sequences of the extracellular portions of such receptors areshown in Table 1 below.

Receptor Extracellular SEQ ID Portion Amino Acid Sequence NO OPGETFPPKYLHYDEETSHQLLCDKCPPGTYLKQHCTAKWKTVCAPCPDHYYTDSWHT 22SDECLYCSPVCKELQYVKQECNRTHNRVCECKEGRYLEIEFCLKHRSCPPGFGVVQ AGTPERNTVCKRCPDGFFSNETSSKAPCRKHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCGIDVTLCEEAFFRFAVPTKFTPNWLSVLVDNLPGTKVNAESVERIKRQHSSQEQTFQL LKLWKHQNKDQDIVKKIIQDIDLCENSVQRHIGHANLTFEQLRSLMESLPGKKVGAEDIEKTIKACKPSDQILKLLSLWRIKNGDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRFLHSFTMYKLYQKLFLEMIGNQVQSVKISCL TACIMSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTI 23CNHQSQRTCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRRQRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKLSADQVALVYS BCMAMLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNA 24 NGFRKEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPC 25KPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSC QDKQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRSTPPEGSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDN EDAREYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCGYGTKDEDYGCVPCPAEKFSKG 26GYQICRRHKDCEGFFRATVLTPGDMENDAECGPCLPGYYIVILENRPRNIYGIVIVCYSCLLAPPNTKECVGATSGASANFPGTSGSSTLSPFQHAHKELSGQGHLATA DCR2ATIPRQDEVPQQTVAPQQQRRSLKEEECPAGSHRSEYTGACNPCTEGVDYTIASN 27 (TNFRSF10D)NLPSCLLCTVCKSGQTNKSSCTTTRDTVCQCEKGSFQDKNSPEMCRTCRTGCPRGMVKVSNCTPRSDIKCKNESAASSTGKTPAAEETVTTILGMLASPYH DCR1ATTARQEEVPQQTVAPQQQRHSFKGEECPAGSHRSEHTGACNPCTEGVDYTNAS 28 (TNFRSF10C)NNEPSCFPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCSRCPSGEVQVSNCTSWDDIQCVEEFGANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTTSPGTPAPAAEETMTTSPGTPAPAAEETMITSPGTPA CD40EPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHC 29HQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCG PQDRLR DR4ASGTEAAAATPSKVWGSSAGRIEPRGGGRGALPTSMGQHGPSARARAGRAPGP 30RPAREASPRLRVHKTFKFVVVGVLLQVVPSSAATIKLHDQSIGTQQWEHSPLGELCPPGSHRSEHPGACNRCTEGVGYTNASNNLFACLPCTACKSDEEERSPCTTTRNTACQCKPGTFRNDNSAEMCRKCSRGCPRGMVKVKDCTPWSDIECVHKESGNGHN DR6QPEQKASNLIGTYRHVDRATGQVLTCDKCPAGTYVSEHCTNTSLRVCSSCPVGTFT 31RHENGIEKCHDCSQPCPWPMIEKLPCAALTDRECTCPPGMFQSNATCAPHTVCPVGWGVRKKGTETEDVRCKQCARGTFSDVPSSVMKCKAYTDCLSQNLVVIKPGTKETDNVCGTLPSFSSSTSPSPGTAIFPRPEHMETHEVPSSTYVPKGMNSTESNSSASVRPKVLSSIQEGTVPDNTSSARGKEDVNKTLPNLQVVNHQQGPHHRHILKLLPSMEATGGEKSSTPIKGPKRGHPRQNLHKHFDINEH DR5ITQQDLAPQQRAAPQQKRSSPSEGLCPPGHHISEDGRDCISCKYGQDYSTHWNDL 32LFCLRCTRCDSGEVELSPCTTTRNTVCQCEEGTFREEDSPEMCRKCRTGCPRGMVKVGDCTPWSDIECVHKESGTKHSGEVPAVEETVTSSPGTPASPCS DR3QGGTRSPRCDCAGDFHKKIGLFCCRGCPAGHYLKAPCTEPCGNSTCLVCPQDTFLA 33WENHHNSECARCQACDEQASQVALENCSAVADTRCGCKPGWFVECQVSQCVSSSPFYCQPCLDCGALHRHTRLLCSRRDTDCGTCLPGFYEHGDGCVSCPTSTLGSCPE RCAAVCGWRQTNFRSF1B LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDS 34CEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLL PMGPSPPAEGSTGDTNFRSF1 LVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTYLYNDCPGPGQDTDCREC 35ESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRHYWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLRENECVSCSNCKKSLECTKLCLPQIENVKGTEDSGTT BMPR1BKKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTS 36GCLGLEGSDFQCRDTPIPHQRRSIECCTERNECNKDLHPTLPPLKNRDFVDGPIHH R BMPR1AQNLDSMLHGTGMKSDSDQKKSENGVTLAPEDTLPFLKCYCSGHCPDDAINNTCIT 37NGHCFAIIEEDDQGETTLASGCMKYEGSDFQCKDSPKAQLRRTIECCRTNLCNQYLQPTLPPVVIGPFFDGSIR BMPR2SQNQERLCAFKDPYQQDLGIGESRISHENGTILCSKGSTCYGLWEKSKGDINLVKQ 38GCWSHIGDPQECHYEECVVTTTPPSIQNGTYRFCCCSTDLCNVNFTENFPPPDTTP LSPPHSFNRDETCSF3R ECGHISVSAPIVHLGDPITASCIIKQNCSHLDPEPQILWRLGAELQPGGRQQRLSDG 39TQESIITLPHLNHTQAFLSCCLNWGNSLQILDQVELRAGYPPAIPHNLSCLMNLTTSSLICQWEPGPETHLPTSFTLKSFKSRGNCQTQGDSILDCVPKDGQSHCCIPRKHLLLYQNMGIWVQAENALGTSMSPQLCLDPMDVVKLEPPMLRTMDPSPEAAPPQAGCLQLCWEPWQPGLHINQKCELRHKPQRGEASWALVGPLPLEALQYELCGLLPATAYTLQIRCIRWPLPGHWSDWSPSLELRTTERAPTVRLDTWWRQRQLDPRTVQLFWKPVPLEEDSGRIQGYVVSWRPSGQAGAILPLCNTTELSCTFHLPSEAQEVALVAYNSAGTSRPTPVVFSESRGPALTRLHAMARDPHSLWVGWEPPNPWPQGYVIEWGLGPPSASNSNKTWRMEQNGRATGFLLKENIRPFQLYEIIVTPLYQDTMGPSQHVYAYSQEMAPSHAPELHLKHIGKTWAQLEWVPEPPELGKSPLTHYTIFWTNAQNQSFSAILNASSRGFVLHGLEPASLYHIHLMAASQAGATNSTVLTLMTLTPEGSELH CSF1RIPVIEPSVPELVVKPGATVTLRCVGNGSVEWDGPPSPHWTLYSDGSSSILSTNNATF 40QNTGTYRCTEPGDPLGGSAAIHLYVKDPARPWNVLAQEVVVFEDQDALLPCLLTDPVLEAGVSLVRVRGRPLMRHTNYSFSPWHGFTIHRAKFIQSQDYQCSALMGGRKVMSISIRLKVQKVIPGPPALTLVPAELVRIRGEAAQIVCSASSVDVNFDVFLQHNNTKLAIPQQSDFHNNRYQKVLTLNLDQVDFQHAGNYSCVASNVQGKHSTSMFFRVVESAYLNLSSEQNLIQEVTVGEGLNLKVMVEAYPGLQGFNWTYLGPFSDHQPEPKLANATTKDTYRHTFTLSLPRLKPSEAGRYSFLARNPGGWRALTFELTLRYPPEVSVIWTFINGSGTLLCAASGYPQPNVTWLQCSGHTDRCDEAQVLQVWDDPYPEVLSQEPFHKVTVQSLLTVETLEHNQTYECRAHNSVGSGSWAFIPISAGAHTHPPDEFLFTP Activin R1AMEDEKPKVNPKLYMCVCEGLSCGNEDHCEGQQCFSSLSINDGFHVYQKGCFQVY 41EQGKMTCKTPPSPGQAVECCQGDWCNRNITAQLPTKGKSFPGTQNFHLE Activin R1BSGPRGVQALLCACTSCLQANYTCETDGACMVSIFNLDGMEHHVRTCIPKVELVPA 42GKPFYCLSSEDLRNTHCCYTDYCNRIDLRVPSGHLKEPEHPSMWGPVE Activin R1CLSPGLKCVCLLCDSSNFTCQTEGACWASVMLTNGKEQVIKSCVSLPELNAQVFCHS 43SNNVTKTECCFTDFCNNITLHLPTASPNAPKLGPME Activin R2BSGRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVK 44KGCWLDDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPP PTAPTLLTActivin R2A AILGRSETQECLFFNANWEKDRTNQTGVEPCYGDKDKRRHCFATWKNISGSIEIVK 45QGCWLDDINCYDRTDCVEKKDSPEVYFCCCEGNMCNEKFSYFPEMEVTQPTSNP VTPKPP TIGITMMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGW 46HISPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAE HGARFQIPFCGR2B TPAAPPKAVLKLEPQWINVLQEDSVTLTCRGTHSPESDSIQWFHNGNLIPTHTQPS 47YRFKANNNDSGEYTCQTGQTSLSDPVHLTVLSEWLVLQTPHLEFQEGETIVLRCHSWKDKPLVKVTFFQNGKSKKFSRSDPNFSIPQANHSHSGDYHCTGNIGYTLYSSKPV TITVQAP FCGR1QVDTTKAVITLQPPWVSVFQEETVTLHCEVLHLPGSSSTQWFLNGTATQTSTPSYR 48ITSASVNDSGEYRCQRGLSGRSDPIQLEIHRGWLLLQVSSRVFTEGEPLALRCHAWKDKLVYNVLYYRNGKAFKFFHWNSNLTILKTNISHNGTYHCSGMGKHRYTSAGISVTVKELFPAPVLNASVTSPLLEGNLVTLSCETKLLLQRPGLQLYFSFYMGSKTLRGRNTSSEYQILTARREDSGLYWCEAATEDGNVLKRSPELELQVLGLQLPTPVWFH 2B4CQGSADHVVSISGVPLQLQPNSIQTKVDSIAWKKLLPSQNGFHHILKWENGSLPSN 49TSNDRFSFIVKNLSLLIKAAQQQDSGLYCLEVTSISGKVQTATFQVFVFESLLPDKVEKPRLQGQGKILDRGRCQVALSCLVSRDGNVSYAWYRGSKLIQTAGNLTYLDEEVDINGTHTYTCNVSNPVSWESHTLNLTQDCQNAHQEFRFWP LAIR1QEEDLPRPSISAEPGTVIPLGSHVTFVCRGPVGVQTFRLERESRSTYNDTEDVSQAS 50PSESEARFRIDSVSEGNAGPYRCIYYKPPKWSEQSDYLELLVKETSGGPDSPDTEPGSSAGPTQRPSDNSHNEHAPASQGLKAEHLY CD5RLSWYDPDFQARLTRSNSKCQGQLEVYLKDGWHMVCSQSWGRSSKQWEDPSQ 51ASKVCQRLNCGVPLSLGPFLVTYTPQSSIICYGQLGSFSNCSHSRNDMCHSLGLTCLEPQKTTPPTTRPPPTTTPEPTAPPRLQLVAQSGGQHCAGVVEFYSGSLGGTISYEAQDKTQDLENFLCNNLQCGSFLKHLPETEAGRAQDPGEPREHQPLPIQWKIQNSSCTSLEHCFRKIKPQKSGRVLALLCSGFQPKVQSRLVGGSSICEGTVEVRQGAQWAALCDSSSARSSLRWEEVCREQQCGSVNSYRVLDAGDPTSRGLFCPHQKLSQCHELWERNSYCKKVFVTCQDPNP TWEAKREQAPGTAPCSRGSSWSADLDKCMDCASCRARPHSDFCLGCAAAPPAPFRLLWP 52

In some embodiments, the extracellular portions of the chimericpolypeptides disclosed herein (e.g., IL-9 switch receptors) having atleast 80% sequence identity, such as, at least 80%, at least 85%, atleast 90%, at least 95%, at least 96%, at least 97%, at least 98%, or99% sequence identity to a sequence selected from the group consistingof SEQ ID NOS: 7-52 in the Sequence Listing. In some embodiments, theextracellular portion includes an amino acid sequence having at least90% sequence identity to a sequence selected from the group consistingof SEQ ID NOS: 7-52. In some embodiments, the extracellular portionincludes an amino acid sequence having at least 95% sequence identity toa sequence selected from the group consisting of SEQ ID NOS: 7-52. Insome embodiments, the extracellular portion includes an amino acidsequence having about 100% sequence identity to a sequence selected fromthe group consisting of SEQ ID NOS: 7-52. In some embodiments, theextracellular portion includes an amino acid sequence having a sequenceselected from the group consisting of SEQ ID NOS: 7-52, wherein one,two, three, four, or five of the amino acid residues in any one of theSEQ ID NOS: 7-52 is substituted by a different amino acid residue.

Transmembrane Domain (TMD)

As outlined above, the chimeric switch receptors of the disclosure alsoinclude a transmembrane domain that joins the extracellular portion andthe intracellular portion of the chimeric receptor.

The transmembrane domain is a region, which can be generallyhydrophobic, and crosses the cell membrane. This domain can bepositioned such that it directly or indirectly connects, or joins, theextracellular portion of the chimeric switch receptor to theintracellular portion of the chimeric switch receptor. This includes,but is not limited to recombinant fusions, covalent bonds, disulfidebonds, ionic bonds, hydrogen bonds, electrostatic bonds, and the like.Transmembrane domains may be a hydrophobic alpha helix that spans thecell membrane. The transmembrane domain associated with the endodomainis commonly used. However, in some embodiments, the transmembrane domainof TNFR1 is used in combination with extracellular portions from the TNFsuperfamily (e.g., DCR2, TNFRSF1, etc.) to stabilize the receptorstructure.

The transmembrane domain can have any length. In some embodiments, thetransmembrane domain includes 1 amino acid or 10 amino acids or 20 aminoacids or 50 amino acids or 60 amino acids or 70 amino acids or 80 aminoacids or 100 amino acids or 120 amino acids or 140 amino acids or 160amino acids or 180 amino acids or 200 amino acids or 250 amino acids or300 amino acids or any number therebetween.

In some embodiments, the transmembrane domain is selected from thetransmembrane domain of IL-9, IL-7ra, IL-2rb, and TNFR1. Exemplary aminosequences of transmembrane domains for use herein are shown in Table 2.

TABLE 2 Transmembrane domain sequences Transmembrane domainAmino acid sequence SEQ ID NO IL-9 LIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPR 53IL-7ra PILLTISILSFFSVALLVILACVLW 54 IL-2rb IPWLGHLLVGLSGAFGFIILVYLLI 55TNFR1 VLLPLVIFFGLCLLSLLFIGLMY 56

In some embodiments, the transmembrane domain comprises thetransmembrane domain of IL-9. In some embodiments, the transmembranedomain comprises the amino acid sequence ofLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPR (SEQ ID NO: 53).

In some embodiments, the transmembrane domain comprises thetransmembrane domain of TNFR1. In some embodiments, the transmembranedomain comprises the amino acid sequence of VLLPLVIFFGLCLLSLLFIGLMY (SEQID NO: 56).

In some embodiments, the transmembrane domain includes an amino acidsequence exhibiting at least 70%, at least 75%, at least 80%, at least85%, at least 90%, at least 95%, at least 96%, at least 97%, at least98%, at least 99% sequence identity to one or more of SEQ ID NOS: 53-56in the Sequence Listing. In some embodiments, the transmembrane domainincludes an amino acid sequence having at least 90% sequence identity toa sequence selected from the group consisting of SEQ ID NOS: 53-56. Insome embodiments, the transmembrane domain includes an amino acidsequence having at least 95% sequence identity to a sequence selectedfrom the group consisting of SEQ ID NOS: 53-56. In some embodiments, thetransmembrane domain includes an amino acid sequence having about 100%sequence identity to one or more of SEQ ID NOS: 53-56. In someembodiments, the transmembrane domain includes an amino acid sequencehaving a sequence selected from the group consisting of SEQ ID NOS:53-56, wherein one, two, three, four, or five of the amino acid residuesin any one of the SEQ ID NOS: 53-56 is substituted by a different aminoacid residue.

Endodomain

In some embodiments, the endodomain is responsible for receptorclustering/dimerization after antigen binding and for initiation ofsignal transduction to the cell.

As outlined above, the chimeric receptors of the disclosure include anendodomain of an IL-9 receptor.

In some embodiments, the amino acid sequence for the IL-9 receptorendodomain is as follows in SEQ ID NO: 57 below:

VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF

In other embodiments, amino acid numbers 292 to 521 of IL-9Rα (NCBIREFSEQ: NP_002177.2) can be used.

Alternatively, a truncated fragment of said endodomain of the IL-9receptor chain also may be used. For example, the truncated fragmentcomprises up to 250 amino acids, or is 50 to 200 amino acids or 80 to150 amino acids of the ILR cytoplasmic domain.

As described supra, one aspect of the present disclosure relates to arecombinant nucleic acid encoding a chimeric receptor including: (a) anextracellular portion comprising a binding domain of an endogenousinhibitory receptor; (b) an intracellular portion comprising anendodomain of an IL-9 receptor linked to a BOX1/2 common gamma chaindomain; (c) a transmembrane domain that joins the extracellular portionand the intracellular portion. Extracellular portions comprising bindingdomains of inhibitory receptors are described above and are useful inthe chimeric receptors described infra as well. In this category ofchimeric receptors, signaling through the IL-9 endodomain requiresrecruitment of the common gamma chain. In some embodiments, the bindingdomains of the extracellular portion of the chimeric receptors describedherein are not able to naturally recruit the common gamma chain in orderto elicit signaling through the IL-9 endodomain of the chimericreceptor. Accordingly, in these embodiments, the endodomain of the IL-9receptor can be linked to BOX1/2 domain. Receptors of the common gammachain family contain two regions at the cytoplasmic tail, termed Box 1and Box 2. These domains are critical for the association of JAKs withthe receptor (see for example, Murakami M, Narazaki M, Hibi M, Yawata H,Yasukawa K, Hamaguchi M, Taga T, Kishimoto T (1991) Critical cytoplasmicregion of the interleukin 6 signal transducer gp130 is conserved in thecytokine receptor family. Proc Natl Acad Sci USA 88:11349-11353).Generally, the Box1 domain contains a proline-rich segment of amino acidresidues, and the Box2 domain contains a hydrophobic segment of aminoacid residues.

In some embodiments, the chimeric receptor comprises a BOX1/2 domain ofthe following amino acid sequence of SEQ ID NO: 58

ERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET

Linkers

The nucleic acid encoding the chimeric receptor can further comprise alinker between any of the portions or domains described above. As usedherein, the term “linker” generally refers to an oligopeptide orpolypeptide that functions to link a one region of a nucleic acid toanother region of a nucleic acid. The spacer or linker may comprise upto 300 amino acids, 0-100 amino acids, 25-50 amino acids, 10-15 aminoacids, for example.

Linkers useful in the chimeric receptors described herein include thosein Table 3 below.

Linker Amino acid sequence SEQ ID NO Gly Ser Linker GGGGSGGGGSGGGGS 59Q-Pro Linker QPQPQPQPQPQP 60 K-Pro Linker KPKPKPKPKPKP 61

In some embodiments, the linker is a Gly Ser Linker. In someembodiments, the linker comprising the amino acid sequenceGGGGSGGGGSGGGGS (SEQ ID NO:59).

In some embodiments, the linker is a Q-Pro Linker. In some embodiments,the linker comprising the amino acid sequence QPQPQPQPQPQP (SEQ IDNO:60).

In some embodiments, no linker is present.

In some embodiments, the linker can be a 2A self-cleaving peptide. 2Apeptide are a class of 18-22 amino acid peptides, which can result inribosomal skipping during translation of a protein in a cell. In someembodiments, a linker, such as a 2A peptide, can be included to link thenucleic acid region encoding the chimeric receptor of the disclosure toanother nucleic acid region encoding a chimeric antigen receptor (CAR).In some embodiments, the CAR is anti-HER2 CAR (4D5).

Signal Sequence

A “signal sequence” can also included at the beginning of the codingsequence of the chimeric receptors disclosed herein. This sequenceencodes a signal peptide, N-terminal to the mature polypeptide, thatdirects the host cell to translocate the polypeptide. Translocationsignal sequences can be found associated with a variety of proteinsnative to eukaryotes and prokaryotes, and are often functional in bothtypes of organisms.

An exemplary signal sequence that can be used in the chimeric receptorsherein includes the amino acid sequence of: MAAPALSWRLPLLILLLPLATSWASA(SEQ ID NO: 62)

Nucleic Acid Molecules

Provided herein are various nucleic acid molecules including nucleotidesequences encoding the chimeric receptors of the disclosure. In someembodiments, expression cassettes and expression vectors contain thesenucleic acid molecules operably linked to heterologous nucleic acidsequences such as, for example, regulatory sequences which allow in vivoexpression of the receptor in a host cell.

The terms “nucleic acid molecule” and “polynucleotide” are usedinterchangeably herein, and refer to both RNA and DNA molecules,including nucleic acid molecules comprising cDNA, genomic DNA, syntheticDNA, and DNA or RNA molecules containing nucleic acid analogs. A nucleicacid molecule can be double-stranded or single-stranded (e.g., a sensestrand or an antisense strand). A nucleic acid molecule may containunconventional or modified nucleotides. The terms “polynucleotidesequence” and “nucleic acid sequence” as used herein interchangeablyrefer to the sequence of a polynucleotide molecule. The nomenclature fornucleotide bases as set forth in 37 CFR § 1.822 is used herein.

Nucleic acid molecules of the present disclosure can be of any length,including for example, between about 1.5 Kb and about 50 Kb, betweenabout 5 Kb and about 40 Kb, between about 5 Kb and about 30 Kb, betweenabout 5 Kb and about 20 Kb, or between about 10 Kb and about 50 Kb, forexample between about 15 Kb to 30 Kb, between about 20 Kb and about 50Kb, between about 20 Kb and about 40 Kb, about 5 Kb and about 25 Kb, orabout 30 Kb and about 50 Kb.

In some embodiments, provided herein is a nucleic acid moleculeincluding a nucleotide sequence encoding a chimeric polypeptideincluding: (a) an extracellular portion comprising a binding domain ofan endogenous cytokine receptor; (b) a transmembrane domain; and (c) anintracellular portion comprising an endodomain of an IL-9 receptor.

In one embodiment, the nucleic acid molecule includes a sequenceencoding a chimeric polypeptide including: (a) a binding domain ofIL-21; (b) a transmembrane domain of IL-9; and (c) an endodomain of anIL-9 receptor.

In one embodiment, the nucleic acid molecule includes a sequenceencoding a chimeric polypeptide including: (a) a binding domain of IL-4;(b) a transmembrane domain of IL-9; and (c) an endodomain of an IL-9receptor.

In one embodiment, the nucleic acid molecule includes a sequenceencoding a chimeric polypeptide including: (a) a binding domain ofIL-15Ra; (b) a transmembrane domain of IL-9; and (c) an endodomain of anIL-9 receptor.

In one embodiment, the nucleic acid molecule includes a sequenceencoding a chimeric polypeptide including: (a) a binding domain ofIL-10Ra; (b) a transmembrane domain of IL-9; and (c) an endodomain of anIL-9 receptor.

In some embodiments, provided herein is a nucleic acid moleculeincluding a nucleotide sequence encoding a chimeric polypeptideincluding: (a) an extracellular portion comprising a binding domain ofan endogenous inhibitory receptor; (b) a transmembrane domain; and (c)an intracellular portion comprising an endodomain of an IL-9 receptorlinked to a BOX1/2 common gamma chain domain.

The orientation of the endodomain of the IL-9 receptor linked to a BOX1/2 common gamma chain domain may be altered depending upon desiredstructure and function. For example, the intracellular portion cancomprise, in an N- to C-terminal direction, an endomain of an IL-9receptor, a linker, and a BOX 1/2 common gamma chain domain.Alternatively, the intracellular portion can comprise, in an N- toC-terminal direction, a BOX 1/2 common gamma chain domain, a linker, andan endomain of an IL-9 receptor.

In one embodiment, the nucleic acid molecule includes a sequenceencoding a chimeric polypeptide including: (a) a binding domain of Fas;(b) a transmembrane domain of IL-9; and (c) an endodomain of an IL-9receptor linked to a BOX1/2 common gamma chain domain.

In some embodiments, provided herein is a nucleic acid moleculeincluding a nucleotide sequence encoding a chimeric polypeptideincluding: (a) an extracellular portion comprising a binding domain ofan endogenous inhibitory receptor linked to an agent specific for thecommon gamma chain; (b) a transmembrane domain; and (c) an intracellularportion comprising an endodomain of an IL-9 receptor.

The orientation of the extracellular portion comprising a binding domainof an endogenous inhibitory receptor linked to an agent specific for thecommon gamma chain may be altered depending upon desired structure andfunction. For example, the extracellular portion can comprise, in an N-to C-terminal direction, a binding domain of an endogenous inhibitoryreceptor, a linker, and an agent specific for the common gamma chain.Alternatively, the extracellular portion can comprise, in an N- toC-terminal direction, an agent specific for the common gamma chain, alinker, and a binding domain of an endogenous inhibitory receptor.

In some embodiments, the nucleotide sequence is incorporated into anexpression cassette or an expression vector. It will be understood thatan expression cassette generally includes a construct of geneticmaterial that contains coding sequences and enough regulatoryinformation to direct proper transcription and/or translation of thecoding sequences in a recipient cell, in vivo and/or ex vivo. Generally,the expression cassette may be inserted into a vector for targeting to adesired host cell and/or into a subject. As such, in some embodiments,an expression cassette of the disclosure include a coding sequence forthe chimeric polypeptide as disclosed herein, which is operably linkedto expression control elements, such as a promoter, and optionally, anyor a combination of other nucleic acid sequences that affect thetranscription or translation of the coding sequence.

In some embodiments, the nucleotide sequence is incorporated into acloning vector or an expression vector. It will be understood by oneskilled in the art that the term “vector” generally refers to arecombinant polynucleotide construct designed for transfer between hostcells, and that may be used for the purpose of transformation, e.g., theintroduction of heterologous DNA into a host cell. As such, in someembodiments, the vector can be a replicon, such as a plasmid, phage, orcosmid, into which another DNA segment may be inserted so as to bringabout the replication of the inserted segment. In some embodiments, theexpression vector can be an integrating vector. In some embodiments, thenucleotide sequence is incorporated into a cloning vector.

As described above in relation to linkers, the nucleic acid sequenceencoding a chimeric receptor as described herein can also encode a CAR.Each may each be provided on separate expression vectors, each nucleicacid sequence being operably linked to one or more expression controlelements to achieve expression of the CAR and chimeric receptor in thetarget cell, the vectors being co-transfected into the target cell.Alternatively, the nucleic acid sequences encoding the CAR and thechimeric receptor may each be provided on a single vector each nucleicacid sequence under the control of one or more expression controlelements to achieve expression of the associated nucleic acid sequence.Alternatively, both nucleic acid sequences may be under the control of asingle promoter with intervening or downstream control elements thatfacilitate co-expression of the two sequences from the vector.

In some embodiments, the expression vector can be a viral vector. Aswill be appreciated by one of skill in the art, the term “viral vector”is widely used to refer either to a nucleic acid molecule (e.g., atransfer plasmid) that includes virus-derived nucleic acid elements thatgenerally facilitate transfer of the nucleic acid molecule orintegration into the genome of a cell or to a viral particle thatmediates nucleic acid transfer. Viral particles will generally includevarious viral components and sometimes also host cell components inaddition to nucleic acid(s). The term viral vector may refer either to avirus or viral particle capable of transferring a nucleic acid into acell or to the transferred nucleic acid itself. Viral vectors andtransfer plasmids contain structural and/or functional genetic elementsthat are primarily derived from a virus. The term “retroviral vector”refers to a viral vector or plasmid containing structural and functionalgenetic elements, or portions thereof, that are primarily derived from aretrovirus. The term “lentiviral vector” refers to a viral vector orplasmid containing structural and functional genetic elements, orportions thereof, including LTRs that are primarily derived from alentivirus, which is a genus of retrovirus.

In some embodiments, provided herein are nucleic acid molecules encodinga polypeptide with an amino acid sequence having at least about 80%,90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a chimericreceptor disclosed herein. In some embodiments, provided herein arenucleic acid molecules encoding a polypeptide with an amino acidsequence having at least about 80%, 90%, 95%, 96%, 97%, 98%, 99%, or100% sequence identity to any one of SEQ ID NOS: 63-203 as identified inthe Sequence Listing.

The nucleic acid sequences encoding the chimeric receptors can beoptimized for expression in the host cell of interest. For example, theG-C content of the sequence can be adjusted to average levels for agiven cell, as calculated by reference to known genes expressed in thehost cell. Methods for codon usage optimization are known in the art.Codon usages within the coding sequence of the chimeric receptordisclosed herein can be optimized to enhance expression in the hostcell, such that about 1%, about 5%, about 10%, about 25%, about 50%,about 75%, or up to 100% of the codons within the coding sequence havebeen optimized for expression in a particular host cell.

Some embodiments disclosed herein relate to vectors or expressioncassettes including a recombinant nucleic acid molecule encoding thechimeric receptors disclosed herein. The expression cassette generallycontains coding sequences and sufficient regulatory information todirect proper transcription and/or translation of the coding sequencesin a recipient cell, in vivo and/or ex vivo. The expression cassette maybe inserted into a vector for targeting to a desired host cell and/orinto a subject. An expression cassette can be inserted into a plasmid,cosmid, virus, autonomously replicating polynucleotide molecule, phage,as a linear or circular, single-stranded or double-stranded, DNA or RNApolynucleotide molecule, derived from any source, capable of genomicintegration or autonomous replication, including a nucleic acid moleculewhere one or more nucleic acid sequences has been linked in afunctionally operative manner, i.e., operably linked. 101601 Alsoprovided herein are vectors, plasmids, or viruses containing one or moreof the nucleic acid molecules encoding a chimeric receptor disclosedherein. The nucleic acid molecules can be contained within a vector thatis capable of directing their expression in, for example, a cell thathas been transformed/transduced with the vector. Suitable vectors foruse in eukaryotic and prokaryotic cells are known in the art and arecommercially available, or readily prepared by a skilled artisan. Seefor example, Sambrook, J., & Russell, D. W. (2012). Molecular Cloning: ALaboratory Manual (4th ed.). Cold Spring Harbor, NY: Cold Spring HarborLaboratory and Sambrook, J., & Russel, D. W. (2001). Molecular Cloning:A Laboratory Manual (3rd ed.). Cold Spring Harbor, NY: Cold SpringHarbor Laboratory (jointly referred to herein as “Sambrook”); Ausubel,F. M. (1987). Current Protocols in Molecular Biology. New York, NY:Wiley (including supplements through 2014); Bollag, D. M. et al. (1996).Protein Methods. New York, NY: Wiley-Liss; Huang, L. et al. (2005).Nonviral Vectors for Gene Therapy. San Diego: Academic Press; Kaplitt,M. G. et al. (1995). Viral Vectors: Gene Therapy and NeuroscienceApplications. San Diego, CA: Academic Press; Lefkovits, I. (1997). TheImmunology Methods Manual: The Comprehensive Sourcebook of Techniques.San Diego, CA: Academic Press; Doyle, A. et al. (1998). Cell and TissueCulture: Laboratory Procedures in Biotechnology. New York, NY: Wiley;Mullis, K. B., Ferre, F. & Gibbs, R. (1994). PCR: The Polymerase ChainReaction. Boston: Birkhauser Publisher; Greenfield, E. A. (2014).Antibodies: A Laboratory Manual (2nd ed.). New York, NY: Cold SpringHarbor Laboratory Press; Beaucage, S. L. et al. (2000). CurrentProtocols in Nucleic Acid Chemistry. New York, NY: Wiley, (includingsupplements through 2014); and Makrides, S. C. (2003). Gene Transfer andExpression in Mammalian Cells. Amsterdam, NL: Elsevier Sciences B. V.,the disclosures of which are incorporated herein by reference).

DNA vectors can be introduced into eukaryotic cells via conventionaltransformation or transfection techniques. Suitable methods fortransforming or transfecting host cells can be found in Sambrook et al.(2012, supra) and other standard molecular biology laboratory manuals,such as, calcium phosphate transfection, DEAE-dextran mediatedtransfection, transfection, microinjection, cationic lipid-mediatedtransfection, electroporation, transduction, scrape loading, ballisticintroduction, nucleoporation, hydrodynamic shock, and infection.

Viral vectors that can be used in the disclosure include, for example,retrovirus vectors, adenovirus vectors, and adeno-associated virusvectors, lentivirus vectors, herpes virus, simian virus 40 (SV40), andbovine papilloma virus vectors (see, for example, Gluzman (Ed.),Eukaryotic Viral Vectors, CSH Laboratory Press, Cold Spring Harbor,N.Y.). For example, a chimeric receptor as disclosed herein can beproduced in a eukaryotic host, such as a mammalian cells (e.g., COScells, NIH 3T3 cells, or HeLa cells). These cells are available frommany sources, including the American Type Culture Collection (Manassas,VA). In selecting an expression system, care should be taken to ensurethat the components are compatible with one another. Artisans ofordinary skill are able to select and design expression systems suitableand functional in a selected engineered cell. If further guidance isrequired in selecting an expression system, skilled artisans may consultP. Jones, “Vectors: Cloning Applications”, John Wiley and Sons, NewYork, N.Y., 2009).

The nucleic acid molecules provided can contain naturally occurringsequences, or sequences that differ from those that occur naturally,but, due to the degeneracy of the genetic code, encode the samepolypeptide, e.g., antibody. These nucleic acid molecules can consist ofRNA or DNA (for example, genomic DNA, cDNA, or synthetic DNA, such asthat produced by phosphoramidite-based synthesis), or combinations ormodifications of the nucleotides within these types of nucleic acids. Inaddition, the nucleic acid molecules can be double-stranded orsingle-stranded (e.g., either a sense or an antisense strand).

Recombinant Cells and Cell Cultures

The nucleic acid of the present disclosure can be introduced into a hostcell, such as, for example, a human T lymphocyte, to produce a host cellcontaining the recombinant nucleic acid molecule. Accordingly, someembodiments of the disclosure relate to methods for making a host cell,including (a) providing a cell capable of protein expression and (b)contacting the provided cell with a recombinant nucleic acid of thedisclosure.

Introduction of the nucleic acid molecules of the disclosure into cellscan be achieved by methods known to those skilled in the art such as,for example, viral infection, transfection, conjugation, protoplastfusion, lipofection, electroporation, nucleofection, calcium phosphateprecipitation, polyethyleneimine (PEI)-mediated transfection,DEAE-dextran mediated transfection, liposome-mediated transfection,particle gun technology, calcium phosphate precipitation, directmicro-injection, nanoparticle-mediated nucleic acid delivery, and thelike.

Accordingly, in some embodiments, the nucleic acid molecules can bedelivered by viral or non-viral delivery vehicles known in the art. Forexample, the nucleic acid molecule can be stably integrated in the hostgenome, or can be episomally replicating, or present in the recombinantcell as a mini-circle expression vector for transient expression.Accordingly, in some embodiments, the nucleic acid molecule ismaintained and replicated in the recombinant cell as an episomal unit.In some embodiments, the nucleic acid molecule is stably integrated intothe genome of the recombinant cell. Stable integration can be achievedusing classical random genomic recombination techniques or with moreprecise techniques such as guide RNA-directed CRISPR/Cas9 genomeediting, or DNA-guided endonuclease genome editing with NgAgo(Natronobacterium gregoryi Argonaute), or TALENs genome editing(transcription activator-like effector nucleases). In some embodiments,the nucleic acid molecule is present in the recombinant cell as amini-circle expression vector for transient expression.

The nucleic acid molecules can be encapsulated in a viral capsid or alipid nanoparticle, or can be delivered by viral or non-viral deliverymeans and methods known in the art, such as electroporation. Forexample, introduction of nucleic acids into cells may be achieved byviral transduction. In a non-limiting example, adeno-associated virus(AAV) is engineered to deliver nucleic acids to target cells via viraltransduction. Several AAV serotypes have been described, and all of theknown serotypes can infect cells from multiple diverse tissue types. AAVis capable of transducing a wide range of species and tissues in vivowith no evidence of toxicity, and it generates relatively mild innateand adaptive immune responses.

Lentiviral-derived vector systems are also useful for nucleic aciddelivery and gene therapy via viral transduction. Lentiviral vectorsoffer several attractive properties as gene-delivery vehicles,including: (i) sustained gene delivery through stable vector integrationinto host genome; (ii) the capability of infecting both dividing andnon-dividing cells; (iii) broad tissue tropisms, including importantgene- and cell-therapy-target cell types; (iv) no expression of viralproteins after vector transduction; (v) the ability to deliver complexgenetic elements, such as polycistronic or intron-containing sequences;(vi) a potentially safer integration site profile; and (vii) arelatively easy system for vector manipulation and production.

In some embodiments, host cells can be genetically engineered (e.g.,transduced or transformed or transfected) with, for example, a vectorconstruct of the present application that can be, for example, a viralvector or a vector for homologous recombination that includes nucleicacid sequences homologous to a portion of the genome of the host cell,or can be an expression vector for the expression of the polypeptides ofinterest. These cells can be either untransformed cells or cells thathave already been transfected with at least one nucleic acid molecule.

In some embodiments, the recombinant cell is a prokaryotic cell or aeukaryotic cell. In some embodiments, the cell is in vivo. In someembodiments, the cell is ex vivo. In some embodiments, the cell is invitro. In some embodiments, the recombinant cell is a prokaryotic cellincluding a recombinant nucleic acid as disclosed herein. In someembodiments, the recombinant prokaryotic cell includes a recombinantnucleic acid which is a cloning vector. In some embodiments, therecombinant cell is a eukaryotic cell. In some embodiments, therecombinant cell is an animal cell. In some embodiments, the animal cellis a mammalian cell. In some embodiments, the animal cell is a humancell. In some embodiments, the cell is a non-human primate cell. In someembodiments, the mammalian cell is an immune cell, a neuron, anepithelial cell, and endothelial cell, or a stem cell. In someembodiments, the recombinant cell is an immune system cell, e.g., alymphocyte (e.g., a T cell or NK cell), or a dendritic cell. In someembodiments, the immune cell is a B cell, a monocyte, a natural killer(NK) cell, a basophil, an eosinophil, a neutrophil, a dendritic cell, amacrophage, a regulatory T cell, a helper T cell (T_(H)), a cytotoxic Tcell (T_(CTL)), or other T cell. In some embodiments, the immune systemcell is a T lymphocyte.

In some embodiments, the cell is a stem cell. In some embodiments, thecell is a hematopoietic stem cell. In some embodiments of the cell, thecell is a lymphocyte. In some embodiments, the cell is a precursor Tcell or a T regulatory (Treg) cell. In some embodiments, the cell is aCD34+, CD8+, or a CD4+ cell. In some embodiments, the cell is a CD8+Tcytotoxic lymphocyte cell selected from the group consisting of naïveCD8+ T cells, central memory CD8+ T cells, effector memory CD8+ T cells,and bulk CD8+ T cells. In some embodiments of the cell, the cell is aCD4+T helper lymphocyte cell selected from the group consisting of naïveCD4+ T cells, central memory CD4+ T cells, effector memory CD4+ T cells,and bulk CD4+ T cells. In some embodiments, the cell can be obtained byleukapheresis performed on a sample obtained from a subject. In someembodiments, the subject is a human patient.

In one embodiment, the cell expressing the recombinant nucleic acidmolecule described herein is a T-cell which has been modified to surfaceexpress a chimeric antigen receptor (a‘CAR-T’ cell). As used herein, aCAR-T cell may be engineered to express a chimeric receptor of thepresent disclosure. CARs useful in the practice of the presentdisclosure can be prepared in accordance with principles well known inthe art. See e.g., Eshhaar et al. U.S. Pat. No. 7,741,465 B1 issued Jun.22, 2010; Sadelain, et al (2013) Cancer Discovery 3(4):388-398; Jensenand Riddell (2015) Current Opinions in Immunology 33:9-15; Gross, et al.(1989) PNAS(USA) 86(24): 10024-10028; Curran, et al. (2012) J Gene Med14(6): 405-15. Examples of commercially available CAR-T cell productsthat may be modified to incorporate a chimeric receptor of the presentdisclosure include axicabtagene ciloleucel (marketed as Yescarta®commercially available from Gilead Pharmaceuticals) and tisagenlecleucel(marketed as Kymriah® commercially available from Novartis).

In some embodiments, the recombinant cell further includes a first and asecond nucleic acid molecule as disclosed herein, wherein the firstnucleic acid molecule and the second nucleic acid molecule do not havethe same sequence. In some embodiments, the recombinant cell furtherincludes a first and a second chimeric polypeptide as disclosed herein,wherein the first chimeric polypeptide and the second chimericpolypeptide do not have the same sequence. In some embodiments, thefirst second chimeric polypeptide is a CAR. In some embodiments, thefirst chimeric polypeptide modulates the expression and/or activity ofthe second chimeric polypeptide.

In some embodiments, the recombinant cell further includes an expressioncassette or vector encoding a protein of interest operably linked to apromoter, wherein expression of the protein is modulated by the chimericreceptor's transcriptional effector. In some embodiments, the protein ofinterest is heterologous to the recombinant cell. In some embodiments,the heterologous protein is one that is not normally found in the cell,e.g., not normally produced by the cell. In some embodiments, theexpression vector encodes a copy of a protein that is already present inthe cell. Exemplary types of proteins suitable for use with thecompositions and methods disclosed herein include cytokines, cytotoxins,chemokines, immunomodulators, pro-apoptotic factors, anti-apoptoticfactors, hormones, differentiation factors, dedifferentiation factors,immune cell receptors, or reporters.

In another aspect, provided herein are compositions of cells comprisingan expression vector described herein. Cell cultures including at leastone host cell as disclosed herein, and a culture medium are alsocontemplated. Generally, the culture medium can be any suitable culturemedium for culturing the cells described herein. Techniques fortransforming a wide variety of the above-mentioned cells and species areknown in the art and described in the technical and scientificliterature. Accordingly, cell cultures including at least onerecombinant cell as disclosed herein are also within the scope of thisapplication. Methods and systems suitable for generating and maintainingcell cultures are known in the art.

Pharmaceutical Compositions

In some embodiments, the nucleic acids, host cells, and/or polypeptides(i.e., chimeric receptors) of the disclosure can be incorporated intocompositions, including pharmaceutical compositions. Such compositionsinclude one or more of the recombinant nucleic acids, host cells, and/orpolypeptides (i.e., chimeric receptors) as disclosed herein. Thecomposition can also contain a pharmaceutically acceptable excipient,e.g., a carrier.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™. (BASF, Parsippany, N.J.), or phosphate buffered saline (PBS). Inall cases, the composition should be sterile and should be fluid to theextent that easy syringability exists. It should be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants,e.g., sodium dodecyl sulfate. Prevention of the action of microorganismscan be achieved by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, andthe like. In many cases, it will be generally to include isotonicagents, for example, sugars, polyalcohols such as mannitol, sorbitol,sodium chloride in the composition. Prolonged absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle, which containsa basic dispersion medium and the required other ingredients from thoseenumerated above.

In some embodiments, the chimeric receptors of the disclosure can alsobe administered by transfection or infection using methods known in theart, including but not limited to the methods described in McCaffrey etal. (Nature 418:6893, 2002), Xia et al. (Nature Biotechnol. 20:1006-10,2002), or Putnam (Am. J. Health Syst. Pharm. 53:151-60, 1996, erratum atAm. J. Health Syst. Pharm. 53:325, 1996).

As described in greater detail below, in some embodiments, the hostcells of the disclosure can be formulated for administration to asubject using techniques known to the skilled artisan. For example,formulations comprising populations of recombinant cells can includepharmaceutically acceptable excipient(s). Excipients included in theformulations will have different purposes depending, for example, on therecombinant cells used and the mode of administration. Examples ofgenerally used excipients included, without limitation: saline, bufferedsaline, dextrose, water-for-injection, glycerol, ethanol, andcombinations thereof, stabilizing agents, solubilizing agents andsurfactants, buffers and preservatives, tonicity agents, bulking agents,and lubricating agents. The formulations comprising recombinant cellscan have been prepared and cultured in the absence of non-humancomponents, e.g., in the absence of animal serum. A formulation caninclude one population of recombinant cells, or more than one, such astwo, three, four, five, six or more populations of recombinant cells.

Formulations comprising population(s) of recombinant cells can beadministered to a subject using modes and techniques known to theskilled artisan. Exemplary modes include, but are not limited to,intravenous injection. Other modes include, without limitation,intratumoral, intradermal, subcutaneous (S.C., s.q., sub-Q, Hypo),intramuscular (i.m.), intraperitoneal (i.p.), intra-arterial,intramedullary, intracardiac, intra-articular (joint), intrasynovial(joint fluid area), intracranial, intraspinal, and intrathecal (spinalfluids). Devices useful for parenteral injection of infusion of theformulations can be used to effect such administration.

Methods of the Disclosure Methods for Modulating an Activity of a Cell

In one aspect, provided herein are methods for modulating an activity ofan immune cell. The methods involve administering, to an immune cell,the recombinant nucleic acid as described herein. One skilled in the artupon reading the present disclosure will appreciate that the disclosedmethods can be carried out in vivo, ex vivo, or in vitro.

Non-limiting exemplary cellular activities that can be modulated usingthe methods provide herein include, but are not limited to, geneexpression, proliferation, apoptosis, non-apoptotic death,differentiation, dedifferentiation, migration, secretion of a geneproduct, cellular adhesion, and cytolytic activity.

In some embodiments, the expression of a gene product of the cell ismodulated.

In some embodiments, the gene product in the cell is selected from thegroup consisting of a chemokine, a chemokine receptor, a chimericantigen receptor, a cytokine, a cytokine receptor, a differentiationfactor, a growth factor, a growth factor receptor, a hormone, ametabolic enzyme, a pathogen-derived protein, a proliferation inducer, areceptor, an RNA guided nuclease, a site-specific nuclease, a T cellreceptor (TCR) or a component thereof, a chimeric antigen receptor(CAR), a toxin, a toxin-derived protein, a transcriptional effector, atranscriptional activator, a transcriptional repressor, a translationregulator, a translational activator, a translational repressor, anactivating immuno-receptor, an antibody, an apoptosis inhibitor, anapoptosis inducer, an engineered T cell receptor, an immuno-activator,an immuno-inhibitor, and an inhibiting immuno-receptor.

In cases where expression of a chemokine or a cytokine is modulated, insome embodiments, the expression of cytokines and chemokines ismodulated such that there is an increase in type-1 polarizationfollowing ligand stimulation relative to controls. Exemplary cytokineand chemokines that can be modulated include, without limitation, FGF2,GMCSF, IFNa, IFNg, IL-10, IL-17, IL-12, IL-2, IL-3, IL-6, IP-10, MIP1a,and RANTES.

Methods of measuring levels of cytokines and chemokines are known in theart. Levels of cytokines and chemokines can be measured, for example, byenzyme-linked immunosorbent assay (ELISA), bead based systems (e.g.Luminex), the Cytokine Bead Array (Pharmingen) and array-based systems(e.g., EMD Biosciences' ProteoPlex).

In some embodiments, the modulation of an activity of an immune cell caninvolve alteration of cell signaling events within the cell. Asdescribed herein, the IL-9 receptor endodomain signals through JAK1 andJAK3 to activate various developmental pathways including STAT1, STAT3,STAT5, MAPK, and PI3K/AKT pathways. Activation of STAT family membersthrough ligand mediated phosphorylation is believed to confer advantagesin effector function, polarization and proliferation to T cells. This,in some embodiments, administration of the recombinant nucleic acidencoding the chimeric switch receptor described herein inducesphosphorylation of STAT1, STAT3, and/or STAT5 when stimulated withligand. Methods for measuring the phosphorylation status of one or moreproteins is known in the art and includes, for example, western blot andphospho flow cytometry as described in the Examples herein.

Cell death (e.g., apoptosis and non-apoptotic cell death) can also bemodulated by the methods described herein. In some embodiments,administration of the recombinant nucleic acid encoding the chimericswitch receptor described herein can result in increased cell death of atarget cell. By way of example, real-time cytotoxicity assays can beused to analyze whether or not cells expressing a chimeric switchreceptor of the present disclosure show increased cytotoxicity whenexposed to ligand. In some embodiments, cells expressing a chimericswitch receptor of the present disclosure demonstrate improved killingof target cells when stimulated with ligand over unstimulated controls.

Methods of Treatment

Administration of any one of the therapeutic compositions describedherein, e.g., chimeric receptors, nucleic acids, host cells, andpharmaceutical compositions, can be used to treat patients for relevantdiseases, such as cancers, autoimmune diseases, and infections. In someembodiments, the recombinant nucleic acids, host cells, andpharmaceutical compositions described herein can be incorporated intotherapeutic agents for use in methods of treating or aiding in thetreatment of a subject who has, who is suspected of having, or who maybe at high risk for developing one or more diseases.

One aspect of the present disclosure is directed to a method of treatinga subject that involves administering, to the subject, a chimeric switchreceptor of the present disclosure or a cell expressing the recombinantnucleic acid of the present disclosure.

In one embodiment, the subject is treated for cancer. A cancer may beany unwanted cell proliferation (or any disease manifesting itself byunwanted cell proliferation), neoplasm or tumor or increased risk of orpredisposition to the unwanted cell proliferation, neoplasm or tumor.The cancer may be benign or malignant and may be primary or secondary(metastatic). A neoplasm or tumor may be any abnormal growth orproliferation of cells and may be located in any tissue. Examples oftissues include the adrenal gland, adrenal medulla, anus, appendix,bladder, blood, bone, bone marrow, brain, breast, cecum, central nervoussystem (including or excluding the brain) cerebellum, cervix, colon,duodenum, endometrium, epithelial cells (e.g. renal epithelia),gallbladder, oesophagus, glial cells, heart, ileum, jejunum, kidney,lacrimal glad, larynx, liver, lung, lymph, lymph node, lymphoblast,maxilla, mediastinum, mesentery, myometrium, nasopharynx, omentum, oralcavity, ovary, pancreas, parotid gland, peripheral nervous system,peritoneum, pleura, prostate, salivary gland, sigmoid colon, skin, smallintestine, soft tissues, spleen, stomach, testis, thymus, thyroid gland,tongue, tonsil, trachea, uterus, vulva, white blood cells.

Tumors to be treated may be nervous or non-nervous system tumors.Nervous system tumors may originate either in the central or peripheralnervous system, e.g. glioma, medulloblastoma, meningioma, neurofibroma,ependymoma, Schwannoma, neurofibrosarcoma, astrocytoma andoligodendroglioma. Non-nervous system cancers/tumors may originate inany other non-nervous tissue, examples include melanoma, mesothelioma,lymphoma, myeloma, leukemia, Non-Hodgkin's lymphoma (NHL), Hodgkin'slymphoma, chronic myelogenous leukemia (CML), acute myeloid leukemia(AML), myelodysplastic syndrome (MDS), cutaneous T-cell lymphoma (CTCL),chronic lymphocytic leukemia (CLL), hepatoma, epidermoid carcinoma,prostate carcinoma, breast cancer, lung cancer, colon cancer, ovariancancer, pancreatic cancer, thymic carcinoma, NSCLC, haematologic cancerand sarcoma. In particular, treatment of melanoma, kidney cancer (e.g.renal carcinoma) or bladder cancer is contemplated.

In some embodiments the cancer is an EBV or HPV positive cancer.

In one embodiment, the subject is treated for autoimmune disease.Exemplary autoimmune diseases include Crohn's disease and MultipleSclerosis.

In one embodiment, the subject is treated for infection. An infectionmay be any infection or infectious disease, e.g. bacterial, viral,fungal, or parasitic infection. In some embodiments it may beparticularly desirable to treat chronic/persistent infections, e.g.where such infections are associated with T cell dysfunction or T cellexhaustion. It is well established that T cell exhaustion is a state ofT cell dysfunction that arises during many chronic infections (includingviral, bacterial and parasitic), as well as in cancer (Wherry NatureImmunology Vol. 12, No. 6, p 492-499, June 2011).

Examples of bacterial infections that may be treated include infectionby Bacillus spp., Bordetella pertussis, Clostridium spp.,Corynebacterium spp., Vibrio chloerae, Staphylococcus spp.,Streptococcus spp. Escherichia, Klebsiella, Proteus, Yersinia, Erwina,Salmonella, Listeria sp, Helicobacter pylori, mycobacteria (e.g.Mycobacterium tuberculosis) and Pseudomonas aeruginosa. For example, thebacterial infection may be sepsis or tuberculosis. Examples of viralinfections that may be treated include infection by Epstein-Barr virus,influenza virus, measles virus, hepatitis B virus (HBV), hepatitis Cvirus (HCV), human immunodeficiency virus (HIV), lymphocyticchoriomeningitis virus (LCMV), Herpes simplex virus and human papillomavirus.

Examples of fungal infections that may be treated include infection byAlternaria sp, Aspergillus sp, Candida sp and Histoplasma sp. The fungalinfection may be fungal sepsis or histoplasmosis. Examples of parasiticinfections that may be treated include infection by Plasmodium species(e.g. Plasmodium falciparum, Plasmodium yoeli, Plasmodium ovale,Plasmodium vivax, or Plasmodium chabaudi chabaudi). The parasiticinfection may be a disease such as malaria, leishmaniasis andtoxoplasmosis

Administration of Recombinant Cells to a Subject

In some embodiments, the methods of the disclosure involve administeringan effective amount or number of the recombinants cells to a subject inneed of such treatment. This administering step can be accomplishedusing any method of implantation delivery in the art. For example, therecombinant cells can be infused directly in the subject's bloodstreamor otherwise administered to the subject.

In some embodiments, the methods disclosed herein include administering,which term is used interchangeably with the terms “introducing”,implanting”, and “transplanting”, recombinant cells into a subject, by amethod or route that results in at least partial localization of theintroduced cells at a desired site such that a desired effect(s) is/areproduced. The recombinant cells or their differentiated progeny can beadministered by any appropriate route that results in delivery to adesired location in the subject where at least a portion of theadministered cells or components of the cells remain viable. The periodof viability of the cells after administration to a subject can be asshort as a few hours, e.g., twenty-four hours, to a few days, to as longas several years, or even the lifetime of the subject, i.e., long-termengraftment.

When provided prophylactically, the recombinant cells described hereincan be administered to a subject in advance of a symptom of a disease orcondition to be treated. Accordingly, in some embodiments theprophylactic administration of a recombinant cell population preventsthe occurrence of symptoms of the disease or condition.

When provided therapeutically in some embodiments, recombinant cells areprovided at (or after) the onset of a symptom or indication of a diseaseor condition, e.g., upon the onset of disease or condition.

For use in the various embodiments described herein, an effective amountof recombinant cells as disclosed herein, can be at least 10² cells, atleast 5×10² cells, at least 10³ cells, at least 5×10³ cells, at least10⁴ cells, at least 5×10⁴ cells, at least 10⁵ cells, at least 2×10⁵cells, at least 3×10⁵ cells, at least 4×10⁵ cells, at least 5×10⁵ cells,at least 6×10⁵ cells, at least 7×10⁵ cells, at least 8×10⁵ cells, atleast 9×10⁵ cells, at least 1×10⁶ cells, at least 2×10⁶ cells, at least3×10⁶ cells, at least 4×10⁶ cells, at least 5×10⁶ cells, at least 6×10⁶cells, at least 7×10⁶ cells, at least 8×10⁶ cells, at least 9×10⁶ cells,or multiples thereof. The recombinant cells can be derived from one ormore donors or can be obtained from an autologous source. In someembodiments, the recombinant cells are expanded in culture prior toadministration to a subject in need thereof.

In some embodiments, the delivery of a recombinant cell composition(e.g., a composition including a plurality of recombinant cellsaccording to any of the cells described herein) into a subject by amethod or route results in at least partial localization of the cellcomposition at a desired site. A composition including recombinant cellscan be administered by any appropriate route that results in effectivetreatment in the subject, e.g., administration results in delivery to adesired location in the subject where at least a portion of thecomposition delivered, e.g., at least 1×10⁴ cells, is delivered to thedesired site for a period of time. Modes of administration includeinjection, infusion, instillation. “Injection” includes, withoutlimitation, intravenous, intramuscular, intra-arterial, intrathecal,intraventricular, intracapsular, intraorbital, intracardiac,intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular,intraarticular, subcapsular, subarachnoid, intraspinal,intracerebrospinal, and intrasternal injection and infusion. In someembodiments, the route is intravenous. For the delivery of cells,delivery by injection or infusion is a standard mode of administration.

In some embodiments, the recombinant cells are administeredsystemically, e.g., via infusion or injection. For example, a populationof recombinant cells are administered other than directly into a targetsite, tissue, or organ, such that it enters, the subject's circulatorysystem and, thus, is subject to metabolism and other similar biologicalprocesses.

The efficacy of a treatment including any of the compositions providedherein for the treatment of a disease or condition can be determined bya skilled clinician. However, one skilled in the art will appreciatethat a treatment is considered effective if any one or all of the signsor symptoms or markers of disease are improved or ameliorated. Efficacycan also be measured by failure of a subject to worsen as assessed bydecreased hospitalization or need for medical interventions (e.g.,progression of the disease is halted or at least slowed). Methods ofmeasuring these indicators are known to those of skill in the art and/ordescribed herein. Treatment includes any treatment of a disease in asubject or an animal (some non-limiting examples include a human, or amammal) and includes: (1) inhibiting the disease, e.g., arresting, orslowing the progression of symptoms; or (2) relieving the disease, e.g.,causing regression of symptoms; and (3) preventing or reducing thelikelihood of the development of symptoms.

In some embodiments of the disclosed methods, the subject is a mammal.In some embodiments, the mammal is a human.

Additional Therapies

As discussed above, the recombinant cells, and pharmaceuticalcompositions described herein can be administered in combination withone or more additional therapeutic agents such as, for example,chemotherapeutics or anti-cancer agents or anti-cancer therapies.Administration “in combination with” one or more additional therapeuticagents includes simultaneous (concurrent) and consecutive administrationin any order. In some embodiments, the one or more additionaltherapeutic agents, chemotherapeutics, anti-cancer agents, oranti-cancer therapies is selected from the group consisting ofchemotherapy, radiotherapy, immunotherapy, hormonal therapy, toxintherapy, and surgery. “Chemotherapy” and “anti-cancer agent” are usedinterchangeably herein. Various classes of anti-cancer agents can beused. Non-limiting examples include: alkylating agents, antimetabolites,anthracyclines, plant alkaloids, topoisomerase inhibitors,podophyllotoxin, antibodies (e.g., monoclonal or polyclonal), tyrosinekinase inhibitors (e.g., imatinib mesylate (Gleevec® or Glivec®)),hormone treatments, soluble receptors and other antineoplastics.

Accordingly, in some embodiments, the disclosed treatment methodsfurther include administering to the subject a second therapy.Generally, the second therapy can be any therapy known in the art.Non-limiting examples of therapies suitable for use in combination withthe therapeutic compositions disclosed herein include chemotherapy,radiotherapy, immunotherapy, hormonal therapy, toxin therapy, andsurgery. In some embodiments, the second therapy includes one or moreadditional therapeutic agents such as, for example, chemotherapeutics oranti-cancer agents or anti-cancer therapies. In some embodiments, thefirst therapy and the second therapy are administered together in thesame composition. In some embodiments, the first therapy and the secondtherapy are administered in separate compositions. In some embodiments,the first therapy and the second therapy are administered at the sametime. In some embodiments, the first therapy and the second therapy areadministered sequentially. In some embodiments, the first therapy isadministered before the second therapy. In some embodiments, the firsttherapy is administered after the second therapy. In some embodiments,the first therapy and the second therapy are administered in rotation.

Systems and Kits

Also provided herein are kits including the recombinant nucleic acids,recombinant cells, or pharmaceutical compositions provided and describedherein as well as written instructions for making and using the same.For example, provided herein, in some embodiments, are kits that includeone or more of the following: (i) a recombinant nucleic acids asdescribed herein, (ii) a recombinant cell as described herein, and (iii)a pharmaceutical composition as described herein. In some embodiments,the systems and/or kits of the disclosure further include one or moresyringes (including pre-filled syringes) and/or catheters (includingpre-filled syringes) used to administer one any of the providedrecombinant nucleic acids, recombinant cells, or pharmaceuticalcompositions to a subject. In some embodiments, a kit can have one ormore additional therapeutic agents that can be administeredsimultaneously or sequentially with the other kit components for adesired purpose, e.g., for modulating an activity of a cell, inhibitinga target cancer cell, or treating a disease in a subject in needthereof.

Any of the above-described systems and kits can further include one ormore additional reagents, where such additional reagents can be selectedfrom: dilution buffers; reconstitution solutions, wash buffers, controlreagents, control expression vectors, negative control polypeptides,positive control polypeptides, reagents for in vitro production of thechimeric receptor polypeptides.

In some embodiments, a system or kit can further include instructionsfor using the components of the kit to practice the methods. Theinstructions for practicing the methods are generally recorded on asuitable recording medium. For example, the instructions can be printedon a substrate, such as paper or plastic, etc. The instructions can bepresent in the kits as a package insert, in the labeling of thecontainer of the kit or components thereof (i.e., associated with thepackaging or sub-packaging), etc. The instructions can be present as anelectronic storage data file present on a suitable computer readablestorage medium, e.g. CD-ROM, diskette, flash drive, etc. In someinstances, the actual instructions are not present in the kit, but meansfor obtaining the instructions from a remote source (e.g., via theinternet), are provided. An example of this embodiment is a kit thatincludes a web address where the instructions can be viewed and/or fromwhich the instructions can be downloaded. As with the instructions, thismeans for obtaining the instructions can be recorded on a suitablesubstrate.

No admission is made that any reference cited herein constitutes priorart. The discussion of the references states what their authors assert,and the inventors reserve the right to challenge the accuracy andpertinence of the cited documents. It will be clearly understood that,although a number of information sources, including scientific journalarticles, patent documents, and textbooks, are referred to herein; thisreference does not constitute an admission that any of these documentsforms part of the common general knowledge in the art.

The discussion of the general methods given herein is intended forillustrative purposes only. Other alternative methods and alternativeswill be apparent to those of skill in the art upon review of thisdisclosure, and are to be included within the spirit and purview of thisapplication.

Throughout this specification, various patents, patent applications andother types of publications (e.g., journal articles, electronic databaseentries, etc.) are referenced. The disclosure of all patents, patentapplications, and other publications cited herein are herebyincorporated by reference in their entirety to the same extent as ifeach individual publication or patent application was specifically andindividually indicated to be incorporated by reference.

EXAMPLES

The practice of the present disclosure will employ, unless otherwiseindicated, conventional techniques of molecular biology, microbiology,cell biology, biochemistry, nucleic acid chemistry, and immunology,which are well known to those skilled in the art. Such techniques areexplained fully in the literature cited above.

Additional embodiments are disclosed in further detail in the followingexamples, which are provided by way of illustration and are not in anyway intended to limit the scope of this disclosure or the claims.

Example 1

Cloning of chimeric receptors. DNA encoding the binding domains ofIL-2rb, IL-2ra, IL-4r, IL-7ra, IL-15ra, IL-21ra, TGF-beta R1, TGF-betaR2, IL-10ra, FAS, CTLA4, LAGS, TIM3, PD1, ILT2, ILT3, ILT4, ILT5, VEGF;the transmembrane domains of IL-9, IL-7ra and IL-2rb; the endodomain ofthe IL-9 receptor; the BOX 1/2 common gamma chain domain; and an agentspecific for the common gamma chain are cloned, in variousconfigurations, into mammalian expression vectors driven by a CMV orelongation factor (EF)-1 promoter. The vector contains a mammalianselection cassette.

Similarly, DNA encoding the binding domains of IL-2rb, IL-2ra, IL-4r,IL-7ra, IL-15ra, IL-21ra, TGF-beta R1, TGF-beta R2, IL-10ra, FAS, CTLA4,LAG3, TIM3, PD1, ILT2, ILT3, ILT4, ILT5, VEGF; the transmembrane domainsof IL-9, IL-7ra and IL-2rb; the endodomain of the IL-9 receptor; the BOX1/2 common gamma chain domain; and an agent specific for the commongamma chain are cloned, in various configurations, into lentiviralvectors.

Example 2

Lentivirus expression. Lentivirus is produced as previously described in[Tiscornia G. et al. Nature Protocols 27 Jun. 2006; doi:10.1038/nprot.2006.37].

Example 3

Assessment of surface expression of chimeric receptors. Mammalianexpression constructs encoding for chimeric receptors are transfectedinto 293 cells using methods well known in the art such as lipofection2000 (Invitrogen) or electroporation. 24 to 48 hours later, cell surfaceexpression is assessed by flow cytometry using fluorescently labeledantibodies specific for the ectodomains chimeric receptors. An examplewould be FITC labeled anti-IL4R antibody for 293 cells transduced withconstruct 73.

Alternatively, Jurkat T cell are transduced with purified lentivirusexpressing the chimeric receptors of interest at an MOI of 20. 24 to 48hours later, cell surface expression is assessed by flow cytometry usingfluorescently labeled antibodies specific for the ectodomains chimericreceptors.

Example 4

Ligand stimulation and STAT5 activation. Transfected 293 cells andvirally transduced Jurkat T cells are stimulated with individual ligandsto analyze the ability of the ligands to bind the chimeric receptors andinduce STAT5 activation. Briefly, after stimulation with ligand forvarious time points, cells are lysed and protein is collected. Thephosphorylation status of STAT5 is analyzed by Western Blot usingphosphor STAT5 specific antibodies and assessed relative to a negativecontrol comprising an empty vector. STAT5 phosphorylation status ofligand activated cells relative to empty vector controls is alsoassessed by flow cytometry as previously described.(http://rhlccflow.facilities.northwestern.edu/files/2011/09/intracellular-phospho-protein-staining.pdf)

Example 5

STAT5 reporter assay. STAT5 reporter assays are done in 293 cells foractivated JAK1-3 induced activity. Cells are seeded in a 48 well plate.The next day, cells are transfected by Lipofectamine 2000 (Invitrogen)with the STAT5-Luciferase vector and an internal control plasmidtogether with other plasmids expressing genes of interest. 24 hourslater, the cells are stimulated with appropriate ligand for various timepoints, then lysed and subjected to internal control fluorescence andluciferase luminescence measurement using a plate reader. The reportergene activity is shown after being normalized against internal controlreadings.

Example 6

Ligand stimulation and cytokine expression. Jurkat T cell are transducedwith purified lentivirus expressing the chimeric receptors of interest.24 to 48 hours later, cells are stimulated with appropriate ligands forvarious time points from 0, 15, 30 45 and 60 minutes. Cells are thencollected for analysis of expression of IFNγ, IL-4, IL-5, IP-10, IL-2,MIP1α, MIP1β, and TNFα using intracellular flow cytometry. Supernatantsfrom the culture are collected analyzed for the expression of 30cytokines and chemokines (Thermo Fisher)(https://www.thermofisher.com/order/catalog/product/LHC6003M#/LHC6003M)by Luminex analysis.

Example 7

Cytotoxicity Assays. The ability of the recombinant nucleic acidsdescribed herein to stimulate CTL cytotoxicity can be measured bymethods known to the skilled person. Cytotoxicity of a T cell to a giventarget cell can be investigated, for example, using any of the methodsreviewed in Zaritskaya et al. Expert Rev Vaccines (2011), 9(6):601-616,hereby incorporated by reference in its entirety. Additionally, theability of the chimeric cytokine receptor to enhanced cell killing of aGPC3 CAR is assessed by measuring cellular killing of cell line targetsin real time by electrical impedance as described in(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834184/). GPC3 CAR(scFv-41BB-CD3) expressing Lentivirus will be purchased from CreativeBiolabs (CAR-M0158-YC) and used to transduce T cells. Briefly, T cellswill be isolated from the PBMC fraction of peripheral blood by negativeselection. Cells will be stimulated with TransAct (Miltenyi) for 72hours in the presence of IL-2 prior to Lentiviral transduction. Cellswill be incubated for 48 hours and CAR expressing cells sorted by FACS.The CAR positive fraction will then be transduced with the chimericcytokine receptor constructs. Cell surface expression of the chimericcytokine receptor will be assessed 48 hours post transduction, by flowcytometry. Cells will be stimulated with the appropriate ligand for anadditional 48 hours, washed and cultured with HEPG2 target cells onXCellegence plates(https://www.agilent.com/en/product/cell-analysis/real-time-cell-analysis/rtca-analyzers/xcelligence-rtca-mp-multiple-plates-741230).Transduced T cells and target cells will be cocultured for 96 hours.Target killing will be measured in real time according to themanufacturer's protocol.

Example 8 Materials and Methods for Examples 9-12

Cloning of chimeric receptors. DNA encoding the binding domains ofvarious endogenous cytokine and inhibitory receptors; the transmembranedomains of IL-9 or TNFR1; the endodomain of the IL-9 receptor; and/orthe BOX 1/2 common gamma chain domain; were cloned, in variousconfigurations, into pTRPE backbone lentiviral transfer plasmid. Somereceptors were co-expressed with anti-HER2 CAR (4D5) via a 2A linkersequence. The 4D5 amino acid sequence is as follows:

(SEQ ID NO: 204) MDFQVQIFSFLLISASVIMSRGDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTGSTSGSGKPGSGEGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTYAMDVWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAATQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR* 

Similarly, DNA encoding the binding domains of IL-21R, IL-15ra, IL-4ra,IL-10ra, IL-7ra, TWEAKR, CTLA4, TIM3, LAG3, PD1, DCR1, CD40, Fas, Dr4,TNFRSF1B, TGFBR2, TIGIT, 2B4; the transmembrane domains of IL-9 andTNFR1; the endodomain of the IL-9 receptor; the BOX 1/2 common gammachain domain; were cloned, in various configurations, into lentiviralvectors.

Assessment of surface expression of chimeric receptors. Lentiviraltransfer plasmids encoding for chimeric receptors were transfected into293 cells using Lipofectamine 3000 and 500 ng of lentiviral expressionplasmids. 24 hours later, cell surface expression was assessed by flowcytometry using fluorescently labeled antibodies specific for theectodomains of the chimeric receptors. Expression of chimeric receptorson primary human T cells was measured by transducing primary human Tcells with a dilution series of lentiviral supernatants and analyzed byflow cytometry 72 hours later.

Lentivirus. Lentiviruses for transduction of primary human CD3+ T cellswere produced in 293T cells by lipofection (Lipofectamine 3000, ThermoFisher Scientific) of transfer and packaging plasmids, and purified byultracentrifugation. T cells activated with human CD3/CD28 Dynabeads(3:1 beads to cell ratio) in the presence of recombinant IL-7 and IL-15were infected with lentiviruses one day after activation, de-beaded onDay 3, and expanded until Day 5.

Flow Cytometry. Flow cytometric detection of chimeric cytokine receptorsand chimeric antigen receptors was performed by incubating lentivirallytransduced primary human T cells with receptor-specific antibodies for20 minutes in room temperature in the dark followed by acquisition of atleast 10,000 events on FACSymphony A3 flow cytometer (BD Biosciences).Data was analyzed with FlowJo software (BD Biosciences). Transientlytransfected 293T cells were treated similarly to detect chimericcytokine receptors and chimeric antigen receptors 24 hours afterlipofection (Lipofectamine 3000, Thermo Fisher Scientific) of 500 ng oflentiviral expression plasmids.

pSTAT Detection. In phosphoflow experiments, transduced human T cellswere stimulated by addition of ligands for 30 minutes at 37° C., and thereaction was terminated by fixation with 1.5% paraformaldehyde (PFA) for15 min at room temperature with agitation. Cells were washed andpermeabilized with ice-cold 100% methanol for 60 minutes on ice orstored at −80° C. overnight. Cells were washed with FACS buffer beforestaining with pSTAT antibodies (Thermo Fisher Scientific) for 1 h at 4°C. in the dark. Cells were washed and analyzed on FACSymphony A3 flowcytometer. Data represent the mean fluorescence intensity (MFI).

xCELLigence Real-Time Cell Analysis. Tumor cell killing was assessedusing the xCELLigence Real-Time Cell Analysis (RTCA) Analyzer (Agilent).SKOV-3 human ovarian adenocarcinoma tumor cells were seeded on a 96-wellxCELLigence E-Plate at 10,000 cells per well. Twenty-four hours later,transduced T cells with or without 48 hours of pre-incubation withligands for switch receptors were added in triplicate at variouseffector-to-target ratios with or without continued ligand stimulation.At the end of the assay, supernatant from each experimental well of theE-Plate was harvested, centrifuged to remove debris, then immediatelyfrozen at −80 C.

Cytokine Multiplex Analysis. Samples were analyzed for cytokines andchemokines using the Milliplex cytokine assay kit (Millipore) as permanufacturer's protocol. Briefly, samples were diluted 1:2.5 assaydiluent buffer and loaded onto a Millipore Multiscreen BV 96-well filterplate. Serial dilutions of cytokine standards were prepared in paralleland added to the plate. Milliplex 42-Plex Cytokine beads were vortexedfor 30 sec. and 25 ul was added to each well with culture supernatants.Samples were then incubated on a plate shaker at 600 rpm in the dark atroom temperature for 2 hours. The plate was applied to a MilliporeMultiscreen Vacuum Manifold, washed twice with 50 μl of assay buffer(PBS, pH7.4, 1% BSA, 0.05% Tween20, 0.05% sodium azide), and each wellresuspended with 75 μl assay buffer. 25 μl of biotinylated Anti-HumanMulti-Cytokine Reporter was added to each well. The plate was incubatedon a plate shaker at 600 rpm in the dark at room temperature for 1.5hours. Streptavidin-Phycoerythrin was diluted 1:12.5 in assay buffer,and then 25 μl was added directly to each well. The plate was incubatedon a plate shaker at 600 rpm in the dark at room temperature for 30minutes. 25 μl of stop solution (0.2% (v/v) formaldehyde in PBS, pH 7.4)was added to each well and incubated at room temperature for 5 minutes.The plate was then applied to the vacuum manifold and each wellresuspended in 125 μl assay buffer and shaken for 1 minute. Assay platewas the transferred to the Bio-Plex Luminex 200 XYP instrument foranalysis. Cytokine concentrations were calculated using Bio-Plex Manager6.2 software with a 5 parameter curve fitting algorithm applied forstandard curve calculations.

Example 9 Chimeric Switch Receptors are Expressed on the Surface ofCells

In order to analyze whether the chimeric switch receptors were able tobe correctly folded and expressed on the surface of cells, 293T cellswere transiently transfected with lentiviral transfer plasmids encodingfor the chimeric switch receptors. 24 hours later, cell surfaceexpression was assessed by flow cytometry. The expression levels ofvarious constructs are shown in Table 4 below.

TABLE 4 Ligand- Trans- Intra- % expression % expression % % double-Sequence binding membrane cellular transduced control positive positiveID domain domain domain Linker sample sample cells cells SEQ63 + IL21RIL9R IL9R N/A 45.4 0.031  45.369 CAR+ SEQ72 + IL4Ra IL9R IL9R N/A 16.70.5 16.2  CAR+ SEQ89 + CTLA4 IL9R IL9R G₄S 28.8 0.72 28.08 CAR+ SEQ90 +CTLA4 IL9R IL9R QP 26.6 0.22 26.38 CAR+ SEQ91 TIM3 IL9R IL9R G₄S 21.53.42 18.08 SEQ93 LAG3 IL9R IL9R QP 1.33 0.13 1.2 SEQ94 LAG3 IL9R IL9RG₄S 3.35 2.25 1.1 SEQ95 + PD1 IL9R IL9R G₄S 18.3 0.49 17.81 CAR+ SEQ96 +PD1 IL9R IL9R QP 12.2 0.21 11.99 CAR+ SEQ109 DCR1 IL9R IL9R G₄S 26 11.214.8 SEQ110 DCR1 IL9R IL9R QP 17.6 7.66 9.94 SEQ111 CD40 IL9R IL9R G₄S24 1.42 22.58 SEQ112 CD40 IL9R IL9R QP 19.2 0.31 18.89 SEQ113 + Fas IL9RIL9R G₄S 22.9 1.1 21.8  CAR+ SEQ114 + Fas IL9R IL9R QP 24.9 1.03 23.87CAR+ SEQ115 DR4 IL9R IL9R G₄S 54.5 34.7 19.8 SEQ116 DR4 IL9R IL9R QP38.3 21.4 16.9 SEQ123 TNFRSF1B IL9R IL9R G₄S 44.9 1.59 43.31 SEQ124TNFRSF1B IL9R IL9R QP 52.2 1.11 51.09 SEQ153 + IL10Ra IL9R IL9R G₄S 19.20.68 18.52 CAR+ SEQ155 TGFBR2 IL9R IL9R G₄S 6.22 0.45 5.77 SEQ156 TGFBR2IL9R IL9R QP 10.7 0.17 10.53 SEQ159 + TIGIT IL9R IL9R G₄S 13.8 0.1613.64 CAR+ SEQ160 + TIGIT IL9R IL9R QP 19.9 0.023  19.877 CAR+ SEQ1652B4 IL9R IL9R G₄S 30.4 28.5 1.9 SEQ166 2B4 IL9R IL9R QP 18.1 15.3 2.8SEQ187 DCR1 TNFR1 IL9R G₄S 35.3 15.5 19.8 SEQ188 DCR1 TNFR1 IL9R QP 4711.4 35.6 SEQ189 CD40 TNFR1 IL9R G₄S 31.1 1.03 30.07 SEQ190 CD40 TNFR1IL9R QP 29 1.45 27.55 SEQ193 DR4 TNFR1 IL9R G₄S 65.8 45.3 20.5 SEQ194DR4 TNFR1 IL9R QP 63.7 49.6 14.1 SEQ200 TNFRSF1B TNFR1 IL9R G₄S 29.11.31 27.79 SEQ201 TNFRSF1B TNFR1 IL9R QP 47.3 0.95 46.35

As demonstrated by the data in Table 4, all constructs exhibited somelevel of cell surface expression in 293T cells. These results indicatethat the constructs produced properly folded proteins capable ofendocytic transport and resistant to general proteolysis.

Constructs that exhibited cell surface expression in 293T cells werethen packaged in lentivirus and titered on human primary T cells. Theexpression analysis over transduced primary human T cells is show inTable 5 below

TABLE 5 % positive % positive T cells in % double- T cells in stainedun- positive unstained transduced Ligand- Trans- Intra- Fold- % T cellsT cells T cells Sequence binding membrane cellular dilution of positive(average of (average of (endogenous ID domain domain domain Linkerlentivirus T cells duplicates) duplicates) expression) SEQ63 + IL21RIL9R IL9R N/A 2 61 0.46 20.6 CAR+ 6 39.85 18 28.4 54 14.8 162 4.725 4860.845 1458 0.495 SEQ66 IL15Ra IL9R IL9R N/A 2 63.1 0.2  32.3 6 60.6 1833.85 54 40.6 162 39.6 486 38 1458 36 SEQ69 IL7Ra IL9R IL9R N/A 2 90.61.02 55.5 6 83.4 18 77.25 54 66.6 162 60.45 486 54.4 1458 52.8 SEQ72 +IL4Ra IL9R IL9R N/A 2 38.95 0.15 44.6 CAR+ 6 29.85 18 18.1 54 10.8 1627.01 486 2.915 1458 1.41 SEQ89 + CTLA4 IL9R IL9R G₄S 2 30 N/A N/A CAR+ 618.45 18 9.895 54 3.97 162 1.355 486 0.635 1458 0.485 SEQ90 + CTLA4 IL9RIL9R QP 2 41.3  0.058  0.63 CAR+ 6 31.5 18 20.05 54 12.6 162 3.06 4861.255 1458 0.68 SEQ91 TIM3 IL9R IL9R G₄S 2 83.4 1.71 88.4 6 84.15 1885.5 54 81.8 162 88.3 486 86.6 1458 77 4374 84.9 SEQ95 + PD1 IL9R IL9RG₄S 2 32.45  0.027  0.64 CAR+ 6 18.75 18 14.45 54 6.965 162 2.43 4861.19 1458 0.88 SEQ96 + PD1 IL9R IL9R QP 2 30.5 0.01 85.8 CAR+ 6 25.1 1812.85 54 9.4 162 3.31 486 1.33 1458 0.645 SEQ109 DCR1 IL9R IL9R G₄S 277.8  0.033  0.7 6 60.95 18 44.6 54 29.45 162 13.4 486 4.285 1458 2.985SEQ110 DCR1 IL9R IL9R QP 2 89.1  0.059  1.14 6 74.9 18 49.65 54 28.9 16215.6 486 10.755 1458 8.61 SEQ111 CD40 IL9R IL9R G₄S 2 50.25 0.44 12.1 648.2 18 38.1 54 40.25 162 21.8 486 9.285 1458 9.3 SEQ112 CD40 IL9R IL9RQP 2 85.05  0.049  3.41 6 78.2 18 62.4 54 39.1 162 31.75 486 13.65 145812.13 SEQ113 + Fas IL9R IL9R G₄S 2 42.45 N/A N/A CAR+ 6 17.3 18 8.735 544.84 162 2.05 486 0.98 1458 0.625 SEQ114 + Fas IL9R IL9R QP 2 87.15 0.3498.1 CAR+ 6 81.25 18 71.4 54 54.15 162 30 486 13 1458 4.52 SEQ116 DR4IL9R IL9R QP 2 93.1 0.2  33.9 6 87.85 18 77.75 54 63.8 162 50.1 486 391458 34.6 SEQ123 TNFRSF1B IL9R IL9R G₄S 2 90.9  0.019 68.5 6 86.45 1877.85 54 57.75 162 78 486 72.45 1458 72.5 SEQ124 TNFRSF1B IL9R IL9R QP 281.05  0.086 72.7 6 78.25 18 70 54 70.75 162 71.9 486 73.6 1458 71.65SEQ154 + IL10Ra IL9R IL9R QP 2 28.2 0.33  1.34 CAR+ 6 22.4 18 10.9 544.49 162 1.635 486 1.055 1458 1.075 SEQ155 TGFBR2 IL9R IL9R G₄S 2 27.550.67  0.68 6 17.6 18 14.14 54 4.305 162 1.425 486 2.1 1458 1.6 SEQ156TGFBR2 IL9R IL9R QP 2 77.45  0.056 68.9 6 76.8 18 70.55 54 70.9 16263.45 486 67.5 1458 71.05 SEQ171 TWEAKR IL9R IL9R G₄S 2 77.35 0.54 62.86 68.45 18 53.65 54 46.8 162 59.7 486 63.4 1458 63.75 SEQ172 TWEAKR IL9RIL9R QP 2 74 0.39 32.9 6 53.85 18 44.9 54 47.4 162 36.45 486 34.75 145834.1 SEQ173 TWEAKR TNFR1 IL9R G₄S 2 92.7 0.37 30.5 6 80.85 18 64.65 5446.55 162 36.1 486 32.95 1458 31 SEQ174 TWEAKR TNFR1 IL9R QP 2 87.2 0.2923.6 6 68.95 18 47.75 54 37.15 162 30 486 25.7 1458 26.75 SEQ187 DCR1TNFR1 IL9R G₄S 2 86.65 0.16  4.81 6 70.25 18 50.15 54 29 162 19.8 4866.475 1458 3.325 SEQ188 DCR1 TNFR1 IL9R QP 2 63.85 0.02  8.63 6 60.8 1848.65 54 35.7 162 15.08 486 14.7 1458 8.65 SEQ189 CD40 TNFR1 IL9R G₄S 291.05  0.079 11.9 6 79 18 55.8 54 24.3 162 20.55 486 10.65 1458 10.365SEQ190 CD40 TNFR1 IL9R QP 2 58.15 0.32 34   6 56.3 18 53.5 54 48.5 16238.65 486 33.15 1458 31.3 SEQ193 DR4 TNFR1 IL9R G₄S 2 86 0.22 40   669.3 18 61 54 50.3 162 48.85 486 47 1458 43.2 SEQ194 DR4 TNFR1 IL9R QP 287  0.089 60.6 6 84.3 18 83.4 54 84.15 162 75.6 486 74 1458 64.85 SEQ200TNFRSF1B TNFR1 IL9R G₄S 2 96.95 1.84 93.6 6 95.35 18 93.65 54 94.25 16292.7 486 91.65 1458 92 SEQ201 TNFRSF1B TNFR1 IL9R QP 2 95.85 0.39 92.8 696.2 18 94.15 54 93.5 162 94.15 486 92.1 1458 93.8

As demonstrated in Table 5 above, lentiviruses for all constructs weresuccessfully produced and transduced primary human T cells exhibited atleast some level of cell surface expression. Despite their generalresistance to viral transduction and sensitivity unfolded proteinresponses (UPR) [Lopez-Soto et al., “Cancer-induced EndoplasmicReticulum Stress in T Cells Subverts Immunosurveillance,” CellMetabolism 28(6):803-805 (2018); Li et al., “The Emerging Roles ofEndoplasmic Reticulum Stress in Balancing Immunity and Tolerance inHealth and Diseases: Mechanisms and Opportunities,” Front. Immunol.Volum 10, Article 3154], the constructs produced properly foldedproteins capable of endocytic transport and resistant to generalproteolysis in primary T cells.

Example 10 Expression of Chimeric Switch Receptors Results inPhosphorylation of Stat Receptors

Some constructs were then tested for their ability to inducephosphorylation of STAT1, STAT3, and/or STAT5. Briefly, primary human Tcells were transduced with a lentiviral vector encoding switch receptorsof SEQ ID NO:63+CAR+(IL21R ECD+IL9R TM+IL9R ICD and CAR 4D5), SEQ IDNO:66 (IL15Ra+IL9R TM+IL9R ICD), SEQ ID NO:72+CAR+(IL4R ECD+IL9R TM+IL9RICD and CAR 4D5), or SEQ ID NO:153+CAR+(IL10Ra ECD+IL9R TM+IL9R ICD andCAR 4D5). Cells transduced with SEQ ID NO:63+CAR+ were left eitherunstimulated or stimulated with 200 ng/mL IL-21 for 30 minutes. Cellstransduced with SEQ ID NO:66 were left either unstimulated or stimulatedwith 200 ng/mL IL-15 for 30 minutes. Cells transduced with SEQ IDNO:72+CAR+ were left either unstimulated or stimulated with 200 ng/mLIL-4 for 30 minutes. Cells transduced with SEQ ID NO:153+CAR+ were lefteither unstimulated or stimulated with 200 ng/mL IL-4 for 30 minutes.The fold increase in gMFI of ligand stimulated versus no stimulation wascalculated and is shown in FIG. 1 .

As shown in FIG. 1 , all constructs induced phosphorylation of STAT1,STAT3, and STAT5 when stimulated with ligand. Activation of STAT familymembers through ligand mediated phosphorylation is believed to conferadvantages in effector function, polarization and proliferation to Tcells.

Example 11 Primary T Cells Expressing Chimeric Switch Receptors ExhibitEnhanced Tumor Cell Killing

Real-time cytotoxicity assays were then used to analyze whether or notcells expressing a chimeric switch receptor of the present disclosurewould show increased cytotoxicity when exposed to ligand. As shown inFIGS. 2-4 , upon stimulation with ligand, cells expressing either SEQ IDNO:63+CAR+(IL21R ECD+IL9R TM+IL9R ICD and CAR 4D5) (FIG. 2 ), SEQ IDNO:72+CAR+(IL4R ECD+IL9R TM+IL9R ICD and CAR 4D5) (FIG. 3 ), or SEQ IDNO:113+CAR+(Fas ECD+IL9R TM+IL9R ICD and CAR 4D5) (FIG. 4 ),demonstrated an increase in killing of SKOV-3 human ovarianadenocarcinoma cells expressing HER2 when preconditioned with ligand ascompared to untransduced, stimulated cells. Consistent with the observedactivation of STAT transcription factors following ligand stimulation, Tcells transduced with hybrid IL9R receptors demonstrated improvedkilling over unstimulated controls. It should be noted that in the caseof Seq ID NO 113, the presence of natural ligand (TNFSF6) increasesbackground killing in the assay. That said, the addition of exogenousligand enhances T cell killing above controls.

Example 12 Primary T Cells Expressing Chimeric Switch Receptors ExhibitIncreased Cytokine and Chemokine Activity

Culture supernatants from primary human T cells transduced with eitherSEQ ID NO:63+CAR+(IL21R ECD+IL9R TM+IL9R ICD and CAR 4D5) (FIG. 5 ) orSEQ ID NO:72+CAR+(IL4R ECD+IL9R TM+IL9R ICD and CAR 4D5) (FIG. 6 ) werethen analyzed for the presence of cytokines and chemokines. Supernatantswere taken from cells stimulated with ligand before the real-timecytotoxicity assay of Example 11 (first bar, “pre”), cells stimulatedwith ligand during the real-time cytotoxicity assay of Example 11(second bar, “post”), or cells stimulated at both points in thereal-time cytotoxicity assay of Example 11 (third bar, “both”). The foldincrease over unstimulated was calculated and is shown in FIGS. 5 and 6. As shown in FIGS. 5 and 6 , several cytokines and chemokines, such asIFNg, FGF2, GMCSF, IL-3, IL-6, IP10, MIP1a, and RANTES, demonstratedincreased production. The magnitude and quality of cytokines producedfollowing ligand stimulation (either “pre”, “post” or “both”) indicatesa robust improvement in T cell response with hybrid-IL9R engagement.Furthermore, the pattern of cytokine response indicates an increase intype-1 polarization following ligand stimulation relative to controls.

FIGS. 7-19 depict results from the same experiment, however, the data isshown in concentration of cytokine or chemokine (in pg·mL) for each ofthe above described experimental conditions. Similarly, the magnitudeand quality of cytokines produced following ligand stimulation (either“pre”, “post” or “both”) indicates a robust improvement in T cellresponse with hybrid-IL9R engagement, and the pattern of cytokineresponse indicates an increase in type-1 polarization following ligandstimulation relative to controls.

Informal Sequence Listing IL21r/IL9R SEQ ID NO: 63 CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQ YEELKDEATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESIKPAPPF NVTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDS SYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSEELKELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLS PRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPA RPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSS SSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDL QGMLLPSVLSKARSWTF IL21r/IL9R/IL7RaTMSEQ ID NO: 64 CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKDEATSCSLHRSAHNATHATYTCHMDVFHFM ADDIFSVNITDQSGNYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQ YRNRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSEE LKEPILLTISILSFFSVALLVILACVLWVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQ DCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYL PQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDH QGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF IL21r/IL9R/IL2RbTM SEQ ID NO: 65CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQ YEELKDEATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESIKPAPPF NVTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDS SYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSEELKEIPWLGHLLVGLSGAFGFIILVYLLIVKRIFYQ NVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALE EEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNY CALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVL SKARSWTF IL15r-alpha/IL9RSEQ ID NO: 66 ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALV HQRPAPPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHES SHGTPSQTTAKNWELTASASHQPPGVYPQGHSDTTLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRV KRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPW KSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSS SNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGM LLPSVLSKARSWTFIL15r-alpha/IL9R/IL7RaTM SEQ ID NO: 67ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKR KAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPAASSPS SNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQPPGVYPQGHSDTT PILLTISILSFFSVALLVILACVLWVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCA GTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQE DWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGL ETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF IL15r-alpha/IL9R/IL2RbTM SEQ ID NO: 68ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKR KAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPAASSPS SNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQPPGVYPQGHSDTT IPWLGHLLVGLSGAFGFIILVYLLIVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCA GTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQE DWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGL ETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF IL7r-alpha/IL9R SEQ ID NO: 69 ESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDPDVNITNLEFEICGALVEVKCLNFRKLQE IYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSVVYREGANDFVVTFNTSHLQKKYV KVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKLQPAAMYEIKVRSIPDHYFKGFWSEWSPSYYFRTPE INNSSGEMDLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNF QTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVL PAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQS SGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF IL7r-alpha/IL9R/IL7RaTM SEQ ID NO: 70ESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSL TCAFEDPDVNITNLEFEICGALVEVKCLNFRKLQEIYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTT IVKPEAPFDLSVVYREGANDFVVTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKL QPAAMYEIKVRSIPDHYFKGFWSEWSPSYYFRTPEINNSSGEMDPILLTISILSFFSVALLVILACVLWV KRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPW KSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSS SNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGM LLPSVLSKARSWTFIL7r-alpha/IL9R/IL2RbTM SEQ ID NO: 71ESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSL TCAFEDPDVNITNLEFEICGALVEVKCLNFRKLQEIYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTT IVKPEAPFDLSVVYREGANDFVVTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKL QPAAMYEIKVRSIPDHYFKGFWSEWSPSYYFRTPEINNSSGEMDIPWLGHLLVGLSGAFGFIILVYLLIV KRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPW KSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSS SNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGM LLPSVLSKARSWTF IL4r-alpha/IL9RSEQ ID NO: 72 MKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRLLYQLVFLLSEAHTCIPENNGGAGCVCHLLMDDVVS ADNYTLDLWAGQQLLWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSNPYPPDNYLYNHLTYAVNIWS ENDPADFRIYNVTYLEPSLRIAASTLKSGISYRARVRAWAQCYNTTWSEWSPSTKWHNSYREPFEQHLIP PWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVL LSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTL AYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLS CDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF IL4r-alpha/IL9R/IL7RaTM SEQ ID NO: 73MKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRL LYQLVFLLSEAHTCIPENNGGAGCVCHLLMDDVVSADNYTLDLWAGQQLLWKGSFKPSEHVKPRAPGNLT VHTNVSDTLLLTWSNPYPPDNYLYNHLTYAVNIWSENDPADFRIYNVTYLEPSLRIAASTLKSGISYRAR VRAWAQCYNTTWSEWSPSTKWHNSYREPFEQHPILLTISILSFFSVALLVILACVLWVKRIFYQNVPSPA MFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGP GTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCY GGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSW TF IL4r-alpha/IL9R/IL2RbTMSEQ ID NO: 74 MKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRLLYQLVFLLSEAHTCIPENNGGAGCVCHLLMDDVVS ADNYTLDLWAGQQLLWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSNPYPPDNYLYNHLTYAVNIWS ENDPADFRIYNVTYLEPSLRIAASTLKSGISYRARVRAWAQCYNTTWSEWSPSTKWHNSYREPFEQHIPW LGHLLVGLSGAFGFIILVYLLIVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTP QGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQ QGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF IL2r-beta Ectodomain /IL9R SEQ ID NO: 75AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQV HAWPDRRRWNQTCELLPVSQASWACNLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLR LMAPISLQVVHVETHRCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPD TQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDTLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKL SPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGP ARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSS SSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHED LQGMLLPSVLSKARSWTFIL2r-beta Ectodomain /IL9R/IL7RaTM SEQ ID NO: 76AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQV HAWPDRRRWNQTCELLPVSQASWACNLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLR LMAPISLQVVHVETHRCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPD TQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDTPILLTISILSFFSVALLVILACVLWVKRIFY QNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVAL EEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNN YCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSV LSKARSWTFIL2r-beta Ectodomain /IL9R/IL2RbTM SEQ ID NO: 77AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQV HAWPDRRRWNQTCELLPVSQASWACNLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLR LMAPISLQVVHVETHRCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPD TQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDTIPWLGHLLVGLSGAFGFIILVYLLIVKRIFY QNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVAL EEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNN YCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSV LSKARSWTF IL2r-alpha Ectodomain/IL9RSEQ ID NO: 78 ELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYMLCTGNSSHSSWDNQCQCTSSATRNTT KQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCREPPPWENEATERIYHFVVGQMVYYQCVQGYRALHR GPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGEEKPQASPEGRPESETSCLVTTTDFQIQTEMAATME TSIFTTEYQLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNF QTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVL PAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQS SGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF IL2r-alpha Ectodomain/IL9R/IL7RaTM SEQ ID NO: 79ELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFR RIKSGSLYMLCTGNSSHSSWDNQCQCTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCR EPPPWENEATERIYHFVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGE EKPQASPEGRPESETSCLVTTTDFQIQTEMAATMETSIFTTEYQPILLTISILSFFSVALLVILACVLWV KRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPW KSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSS SNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGM LLPSVLSKARSWTFIL2r-alpha Ectodomain/IL9R/IL2RbTM SEQ ID NO: 80ELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFR RIKSGSLYMLCTGNSSHSSWDNQCQCTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCR EPPPWENEATERIYHFVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGE EKPQASPEGRPESETSCLVTTTDFQIQTEMAATMETSIFTTEYQIPWLGHLLVGLSGAFGFIILVYLLIV KRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPW KSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSS SNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGM LLPSVLSKARSWTF ILT5/IL9R/cGC-FSEQ ID NO: 81 GPFPKPTLWAEPGSVISWGSPVTIWCQGSQEAQEYRLHKEGSPEPLDRNNPLEPKNKARFSIPSMTEHHA GRYRCHYYSSAGWSEPSDPLEMVMTGAYSKPTLSALPSPVVASGGNMTLRCGSQKGYHHFVLMKEGEHQL PRTLDSQQLHSRGFQALFPVGPVTPSHRWRFTCYYYYTNTPWVWSHPSDPLEILPSGVSRKPSLLTLQGP VLAPGQSLTLQCGSDVGYNRFVLYKEGERDFLQRPGQQPQAGLSQANFTLGPVSPSNGGQYRCYGAHNLS SEWSAPSDPLNILMAGQIYDTVSLSAQPGPTVASGENVTLLCQSWWQFDTFLLTKEGAAHPPLRLRSMYG AHKYQAEFPMSPVTSAHAGTYRCYGSYSSNPHLLSHPSEPLELVVSGHSGGSSLPPTGPPSTPGLGRYLE LIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGA GVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRV QTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALAC GLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPR IPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWA PPCYTLKPET ILT5/IL9R/cGC-SSEQ ID NO: 82 GPFPKPTLWAEPGSVISWGSPVTIWCQGSQEAQEYRLHKEGSPEPLDRNNPLEPKNKARFSIPSMTEHHA GRYRCHYYSSAGWSEPSDPLEMVMTGAYSKPTLSALPSPVVASGGNMTLRCGSQKGYHHFVLMKEGEHQL PRTLDSQQLHSRGFQALFPVGPVTPSHRWRFTCYYYYTNTPWVWSHPSDPLEILPSGVSRKPSLLTLQGP VLAPGQSLTLQCGSDVGYNRFVLYKEGERDFLQRPGQQPQAGLSQANFTLGPVSPSNGGQYRCYGAHNLS SEWSAPSDPLNILMAGQIYDTVSLSAQPGPTVASGENVTLLCQSWWQFDTFLLTKEGAAHPPLRLRSMYG AHKYQAEFPMSPVTSAHAGTYRCYGSYSSNPHLLSHPSEPLELVVSGHSGGSSLPPTGPPSTPGLGRYLE LIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGA GVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRV QTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALAC GLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPT LKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPC YTLKPET ILT3/IL9R/cGC-FSEQ ID NO: 83 QAGPLPKPTLWAEPGSVISWGNSVTIWCQGTLEAREYRLDKEESPAPWDRQNPLEPKNKARFSIPSMTED YAGRYRCYYRSPVGWSQPSDPLELVMTGAYSKPTLSALPSPLVTSGKSVTLLCQSRSPMDTFLLIKERAA HPLLHLRSEHGAQQHQAEFPMSPVTSVHGGTYRCFSSHGFSHYLLSHPSDPLELIVSGSLEDPRPSPTRS VSTAAGPEDQPLMPTGSVPHSGLRRHWELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQN VPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEE EQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYC ALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLS KARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCL VSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET ILT3/IL9R/cGC-S SEQ ID NO: 84 QAGPLPKPTLWAEPGSVISWGNSVTIWCQGTLEAREYRLDKEESPAPWDRQNPLEPKNKARFSIPSMTED YAGRYRCYYRSPVGWSQPSDPLELVMTGAYSKPTLSALPSPLVTSGKSVTLLCQSRSPMDTFLLIKERAA HPLLHLRSEHGAQQHQAEFPMSPVTSVHGGTYRCFSSHGFSHYLLSHPSDPLELIVSGSLEDPRPSPTRS VSTAAGPEDQPLMPTGSVPHSGLRRHWELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQN VPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEE EQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYC ALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLS KARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSE IPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETILT4 IL9R/cGC-F SEQ ID NO: 85 QTGTIPKPTLWAEPDSVITQGSPVTLSCQGSLEAQEYRLYREKKSASWITRIRPELVKNGQFHIPSITWE HTGRYGCQYYSRARWSELSDPLVLVMTGAYPKPTLSAQPSPVVTSGGRVTLQCESQVAFGGFILCKEGEE EHPQCLNSQPHARGSSRAIFSVGPVSPNRRWSHRCYGYDLNSPYVWSSPSDLLELLVPGVSKKPSLSVQP GPVVAPGESLTLQCVSDVGYDRFVLYKEGERDLRQLPGRQPQAGLSQANFTLGPVSRSYGGQYRCYGAHN LSSECSAPSDPLDILITGQIRGTPFISVQPGPTVASGENVTLLCQSWRQFHTFLLTKAGAADAPLRLRSI HEYPKYQAEFPMSPVTSAHAGTYRCYGSLNSDPYLLSHPSEPLELVVSGPSMGSSPPPTGPISTPAGPED QPLTPTGSDPQSGLGRHLGVLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFF QPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTR LPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGW HLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFG GGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKG GALGEGPGASPCNQHSPYWAPPCYTLKPETILT4 IL9R/cGC-S SEQ ID NO: 86 QTGTIPKPTLWAEPDSVITQGSPVTLSCQGSLEAQEYRLYREKKSASWITRIRPELVKNGQFHIPS ITWEHTGRYGCQYYSRARWSELSDPLVLVMTGAYPKPTLSAQPSPVVTSGGRVTLQCESQVAFG GFILCKEGEEEHPQCLNSQPHARGSSRAIFSVGPVSPNRRWSHRCYGYDLNSPYVWSSPSDLLELLVPGV SKKPSLSVQPGPVVAPGESLTLQCVSDVGYDRFVLYKEGERDLRQLPGRQPQAGLSQANFTLGPVSRSYG GQYRCYGAHNLSSECSAPSDPLDILITGQIRGTPFISVQPGPTVASGENVTLLCQSWRQFHTFLLTKAGA ADAPLRLRSIHEYPKYQAEFPMSPVTSAHAGTYRCYGSLNSDPYLLSHPSEPLELVVSGPSMGSSPPPTG PISTPAGPEDQPLTPTGSDPQSGLGRHLGVLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFY QNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVAL EEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNN YCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSV LSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLV SEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET ILT2 IL9R/cGC-F SEQ ID NO: 87 GHLPKPTLWAEPGSVITQGSPVTLRCQGGQETQEYRLYREKKTALWITRIPQELVKKGQFPIPSITWEHA GRYRCYYGSDTAGRSESSDPLELVVTGAYIKPTLSAQPSPVVNSGGNVILQCDSQVAFDGFSLCKEGEDE HPQCLNSQPHARGSSRAIFSVGPVSPSRRWWYRCYAYDSNSPYEWSLPSDLLELLVLGVSKKPSLSVQPG PIVAPEETLTLQCGSDAGYNRFVLYKDGERDFLQLAGAQPQAGLSQANFTLGPVSRSYGGQYRCYGAHNL SSEWSAPSDPLDILIAGQFYDRVSLSVQPGPTVASGENVTLLCQSQGWMQTFLLTKEGAADDPWRLRSTY QSQKYQAEFPMGPVTSAHAGTYRCYGSQSSKPYLLTHPSDPLELVVSGPSGGPSSPTTGPTSTSGPEDQP LTPTGSDPQSGLGRHLGVLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQP LYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLP GNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHL SALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGG GSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGA LGEGPGASPCNQHSPYWAPPCYTLKPETILT2 IL9R/cGC-S SEQ ID NO: 88 GHLPKPTLWAEPGSVITQGSPVTLRCQGGQETQEYRLYREKKTALWITRIPQELVKKGQFPIPSITWEHA GRYRCYYGSDTAGRSESSDPLELVVTGAYIKPTLSAQPSPVVNSGGNVILQCDSQVAFDGFSLCKEGEDE HPQCLNSQPHARGSSRAIFSVGPVSPSRRWWYRCYAYDSNSPYEWSLPSDLLELLVLGVSKKPSLSVQPG PIVAPEETLTLQCGSDAGYNRFVLYKDGERDFLQLAGAQPQAGLSQANFTLGPVSRSYGGQYRCYGAHNL SSEWSAPSDPLDILIAGQFYDRVSLSVQPGPTVASGENVTLLCQSQGWMQTFLLTKEGAADDPWRLRSTY QSQKYQAEFPMGPVTSAHAGTYRCYGSQSSKPYLLTHPSDPLELVVSGPSGGPSSPTTGPTSTSGPEDQP LTPTGSDPQSGLGRHLGVLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQP LYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLP GNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHL SALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQ PQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGE GPGASPCNQHSPYWAPPCYTLKPETCTLA4 IL9R/cGC-F SEQ ID NO: 89 KAMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTG TSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDLIPPWGWPGNTLVA VSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQG ALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPT SLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQG VAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEY HGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET CTLA4 IL9R/cGC-S SEQ ID NO: 90KAMHVAQPAVVLASSRGIASFVCEYASPGKATEVR VTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYY LGIGNGTQIYVIDPEPCPDSDLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMF FQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGT RLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGG WHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF QPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGA LGEGPGASPCNQHSPYWAPPCYTLKPETTIM3/IL9R/cGC-F SEQ ID NO: 91 SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSRYWLNGDFRKG DVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAE TQTLGSLPDINLTQISTLANELRDSRLANDLRDSGATIRIGLIPPWGWPGNTLVAVSIFLLLTGPTYLLF KLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTC GPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRS SSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLH EDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLA ESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TIM3/IL9R/cGC-S SEQ ID NO: 92SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKG ACPVFECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPG IMNDEKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANELRDS RLANDLRDSGATIRIGLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLY SVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGN LSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSA LPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQ PQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGP GASPCNQHSPYWAPPCYTLKPETLAG3/IL9R/cGC-S SEQ ID NO: 93 LQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSW GPRPRRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRL RLRLGQASMTASPPGSLRASDWVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVS PMDSGPWGCILTYRDGFNVSIMYNLTVLGLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPG GGPDLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVT PVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPGAQRSGRAP GALPAGHLLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQ TWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLP AGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS GPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPE RTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQH SPYWAPPCYTLKPET LAG3/IL9R/cGC-FSEQ ID NO: 94 LQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSW GPRPRRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRL RLRLGQASMTASPPGSLRASDWVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVS PMDSGPWGCILTYRDGFNVSIMYNLTVLGLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPG GGPDLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVT PVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPGAQRSGRAP GALPAGHLLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQ TWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLP AGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS GPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGG GSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPC NQHSPYWAPPCYTLKPET PD1/IL9R/cGC-FSEQ ID NO: 95 FTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLL KDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVISEHELICOAE GYPKAEVIWISSDHQVLSGKTTTTNSKREEKLFNVISILRINTTTNEIFYCTFRRLDPEENHTAELVIPE LPLAHPPNERLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGN FQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDV LPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQ SSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSG GGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGAS PCNQHSPYWAPPCYTLKPET PD1/IL9R/cGC-SSEQ ID NO: 96 FTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLL KDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVISEHELICOAE GYPKAEVIWISSDHQVLSGKTTTTNSKREEKLFNVISILRINTTTNEIFYCTFRRLDPEENHTAELVIPE LPLAHPPNERLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGN FQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDV LPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQ SSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQ PERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCN QHSPYWAPPCYTLKPET OPG/IL9R/cGC-FSEQ ID NO: 97 ETFPPKYLHYDEETSHQLLCDKCPPGTYLKQHCTAKWKTVCAPCPDHYYTDSWHTSDECLYCSPVCKELQ YVKQECNRTHNRVCECKEGRYLEIEFCLKHRSCPPGFGVVQAGTPERNTVCKRCPDGFFSNETSSKAPCR KHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCGIDVTLCEEAFFRFAVPTKFTPNWLSVLVDNLPGTK VNAESVERIKRQHSSQEQTFQLLKLWKHQNKDQDIVKKIIQDIDLCENSVQRHIGHANLTFEQLRSLMES LPGKKVGAEDIEKTIKACKPSDQILKLLSLWRIKNGDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRF LHSFTMYKLYQKLFLEMIGNQVQSVKISCLLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFY QNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVAL EEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNN YCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSV LSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERL CLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET OPG/IL9R/cGC-S SEQ ID NO: 98 ETFPPKYLHYDEETSHQLLCDKCPPGTYLKQHCTAKWKTVCAPCPDHYYTDSWHTSDECLYCSPVCKELQ YVKQECNRTHNRVCECKEGRYLEIEFCLKHRSCPPGFGVVQAGTPERNTVCKRCPDGFFSNETSSKAPCR KHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCGIDVTLCEEAFFRFAVPTKFTPNWLSVLVDNLPGTK VNAESVERIKRQHSSQEQTFQLLKLWKHQNKDQDIVKKIIQDIDLCENSVQRHIGHANLTFEQLRSLMES LPGKKVGAEDIEKTIKACKPSDQILKLLSLWRIKNGDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRF LHSFTMYKLYQKLFLEMIGNQVQSVKISCLLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFY QNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVAL EEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNN YCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSV LSKARSWTFOPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLV SEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TACI/IL9R/cGC-F SEQ ID NO: 99 MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLS CRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRRQRSGEVENNSDNSGRYQGLE HRGSEASPALPGLKLSADQVALVYSLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQE GPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALG CYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKAR SWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSE IPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETTACI/IL9R/cGC-S SEQ ID NO: 100 MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLS CRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRRQRSGEVENNSDNSGRYQGLE HRGSEASPALPGLKLSADQVALVYSLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQE GPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALG CYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKAR SWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPP KGGALGEGPGASPCNQHSPYWAPPCYTLKPETBCMA/IL9R/cGC-F SEQ ID NO: 101 MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNALIPPWGWPGNTLVAVS IFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGAL EPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSL TRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVA WVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHG NFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET BCMA/IL9R/cGC-S SEQ ID NO: 102MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPL TCQRYCNASVTNSVKGTNALIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQ PLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRL PGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWH LSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQP QPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALG EGPGASPCNQHSPYWAPPCYTLKPETNGFR/IL9R/cGC-F SEQ ID NO: 103 KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAP CVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEECPDGTYSDEANHVDPCLPCT VCEDTERQLRECTRWADAECEEIPGRWITRSTPPEGSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGS SQPVVTRGTTDNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHN GNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSE DVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGN TQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGG SGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPG ASPCNQHSPYWAPPCYTLKPETNGFR/IL9R/cGC-S SEQ ID NO: 104 KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAP CVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEECPDGTYSDEANHVDPCLPCT VCEDTERQLRECTRWADAECEEIPGRWITRSTPPEGSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGS SQPVVTRGTTDNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHN GNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSE DVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGN TQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQ PQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASP CNQHSPYWAPPCYTLKPET EDAR/IL9R/cGC-FSEQ ID NO: 105 EYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCGYGTKDEDYGCVPCPAEKFSKGGYQICRRHKDCEGF FRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTKECVGATSGASANFPGTSGSS TLSPFQHAHKELSGQGHLATALIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMF FQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGT RLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGG WHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF GGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPK GGALGEGPGASPCNQHSPYWAPPCYTLKPETEDAR/IL9R/cGC-S SEQ ID NO: 106 EYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCGYGTKDEDYGCVPCPAEKFSKGGYQICRRHKDCEGF FRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTKECVGATSGASANFPGTSGSS TLSPFQHAHKELSGQGHLATALIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMF FQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGT RLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGG WHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF QPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGA LGEGPGASPCNQHSPYWAPPCYTLKPETDCR2 (TNFRSF10D)/IL9R/cGC-F SEQ ID NO: 107ATIPRQDEVPQQTVAPQQQRRSLKEEECPAGSHRS EYTGACNPCTEGVDYTIASNNLPSCLLCTVCKSGQTNKSSCTTTRDTVCQCEKGSFQDKNSPEMCRTCRT GCPRGMVKVSNCTPRSDIKCKNESAASSTGKTPAAEETVTTILGMLASPYHLIPPWGWPGNTLVAVSIFL LLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPC VQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRP APPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVL AGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFS AWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DCR2 (TNFRSF10D)/IL9R/cGC-S SEQ ID NO: 108ATIPRQDEVPQQTVAPQQQRRSLKEEECPAGSHRS EYTGACNPCTEGVDYTIASNNLPSCLLCTVCKSGQTNKSSCTTTRDTVCQCEKGSFQDKNSPEMCRTCRT GCPRGMVKVSNCTPRSDIKCKNESAASSTGKTPAAEETVTTILGMLASPYHLIPPWGWPGNTLVAVSIFL LLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPC VQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRP APPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVL AGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWS GVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DCR1 (TNFRSF10C) /IL9R/cGC-F SEQ ID NO: 109ATTARQEEVPQQTVAPQQQRHSFKGEECPAGSHRS EHTGACNPCTEGVDYTNASNNEPSCFPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCSR CPSGEVQVSNCTSWDDIQCVEEFGANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTT SPGTPAPAAEETMTTSPGTPAPAAEETMITSPGTPALIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPR VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARP WKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSS SSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQG MLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQP DYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DCR1 (TNFRSF10C) /IL9R/cGC-S SEQ ID NO: 110ATTARQEEVPQQTVAPQQQRHSFKGEECPAGSHRS EHTGACNPCTEGVDYTNASNNEPSCFPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCSR CPSGEVQVSNCTSWDDIQCVEEFGANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTT SPGTPAPAAEETMTTSPGTPAPAAEETMITSPGTPALIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPR VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARP WKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSS SSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQG MLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYS ERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET CD40/IL9R/cGC-F SEQ ID NO: 111EPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFT ETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSC SPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRLI PPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGV LLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQT LAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGL SCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIP TLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPP CYTLKPET CD40/IL9R/cGC-SSEQ ID NO: 112 EPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLR VQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEK CHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKR IFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKS VALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSN NNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLL PSVLSKARSWTFOPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERL CLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET FAS/IL9R/cGC-F SEQ ID NO: 113 QVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKA HFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKC KEEGSRSNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQ TWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLP AGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS GPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGG GSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPC NQHSPYWAPPCYTLKPET FAS/IL9R/cGC-SSEQ ID NO: 114 QVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKA HFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKC KEEGSRSNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQ TWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLP AGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS GPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPE RTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQH SPYWAPPCYTLKPET DR4/IL9R/cGC-FSEQ ID NO: 115 ASGTEAAAATPSKVWGSSAGRIEPRGGGRGALPTSMGQHGPSARARAGRAPGPRPAREASPRLRVHKTFK FVVVGVLLQVVPSSAATIKLHDQSIGTQQWEHSPLGELCPPGSHRSEHPGACNRCTEGVGYTNASNNLFA CLPCTACKSDEEERSPCTTTRNTACQCKPGTFRNDNSAEMCRKCSRGCPRGMVKVKDCTPWSDIECVHKE SGNGHNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTW MGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAG CTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGP IPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGS ERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQ HSPYWAPPCYTLKPET DR4/IL9R/cGC-SSEQ ID NO: 116 ASGTEAAAATPSKVWGSSAGRIEPRGGGRGALPTSMGQHGPSARARAGRAPGPRPAREASPRLRVHKTFK FVVVGVLLQVVPSSAATIKLHDQSIGTQQWEHSPLGELCPPGSHRSEHPGACNRCTEGVGYTNASNNLFA CLPCTACKSDEEERSPCTTTRNTACQCKPGTFRNDNSAEMCRKCSRGCPRGMVKVKDCTPWSDIECVHKE SGNGHNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTW MGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAG CTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGP IPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERT MPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSP YWAPPCYTLKPET DR6/IL9R/cGC-FSEQ ID NO: 117 QPEQKASNLIGTYRHVDRATGQVLTCDKCPAGTYVSEHCTNTSLRVCSSCPVGTFTRHENGIEKCHDCSQ PCPWPMIEKLPCAALTDRECTCPPGMFQSNATCAPHTVCPVGWGVRKKGTETEDVRCKQCARGTFSDVPS SVMKCKAYTDCLSQNLVVIKPGTKETDNVCGTLPSFSSSTSPSPGTAIFPRPEHMETHEVPSSTYVPKGM NSTESNSSASVRPKVLSSIQEGTVPDNTSSARGKEDVNKTLPNLQVVNHQQGPHHRHILKLLPSMEATGG EKSSTPIKGPKRGHPRQNLHKHFDINEHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQN VPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEE EQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYC ALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLS KARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCL VSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DR6/IL9R/cGC-S SEQ ID NO: 118 QPEQKASNLIGTYRHVDRATGQVLTCDKCPAGTYVSEHCTNTSLRVCSSCPVGTFTRHENGIEKCHDCSQ PCPWPMIEKLPCAALTDRECTCPPGMFQSNATCAPHTVCPVGWGVRKKGTETEDVRCKQCARGTFSDVPS SVMKCKAYTDCLSQNLVVIKPGTKETDNVCGTLPSFSSSTSPSPGTAIFPRPEHMETHEVPSSTYVPKGM NSTESNSSASVRPKVLSSIQEGTVPDNTSSARGKEDVNKTLPNLQVVNHQQGPHHRHILKLLPSMEATGG EKSSTPIKGPKRGHPRQNLHKHFDINEHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQN VPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEE EQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYC ALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLS KARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSE IPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETDR5/IL9R/cGC-F SEQ ID NO: 119 ITQQDLAPQQRAAPQQKRSSPSEGLCPPGHHISEDGRDCISCKYGQDYSTHWNDLLFCLRCTRCDSGEVE LSPCTTTRNTVCQCEEGTFREEDSPEMCRKCRTGCPRGMVKVGDCTPWSDIECVHKESGTKHSGEVPAVE ETVTSSPGTPASPCSLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYS VHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNL SSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSAL PGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSG GGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGE GPGASPCNQHSPYWAPPCYTLKPETDR5/IL9R/cGC-S SEQ ID NO: 120 ITQQDLAPQQRAAPQQKRSSPSEGLCPPGHHISEDGRDCISCKYGQDYSTHWNDLLFCLRCTRCDSGEVE LSPCTTTRNTVCQCEEGTFREEDSPEMCRKCRTGCPRGMVKVGDCTPWSDIECVHKESGTKHSGEVPAVE ETVTSSPGTPASPCSLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYS VHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNL SSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSAL PGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQP QPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPG ASPCNQHSPYWAPPCYTLKPETDR3/IL9R/cGC-F SEQ ID NO: 121 QGGTRSPRCDCAGDFHKKIGLFCCRGCPAGHYLKAPCTEPCGNSTCLVCPQDTFLAWENHHNSECARCQA CDEQASQVALENCSAVADTRCGCKPGWFVECQVSQCVSSSPFYCQPCLDCGALHRHTRLLCSRRDTDCGT CLPGFYEHGDGCVSCPTSTLGSCPERCAAVCGWRQLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRV KRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPW KSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSS SNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGM LLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPD YSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DR3/IL9R/cGC-S SEQ ID NO: 122QGGTRSPRCDCAGDFHKKIGLFCCRGCPAGHYLKA PCTEPCGNSTCLVCPQDTFLAWENHHNSECARCQACDEQASQVALENCSAVADTRCGCKPGWFVECQVSQ CVSSSPFYCQPCLDCGALHRHTRLLCSRRDTDCGTCLPGFYEHGDGCVSCPTSTLGSCPERCAAVCGWRQ LIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGA GVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRV QTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALAC GLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPT LKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPC YTLKPET TNFRSF1B/IL9R/cGC-FSEQ ID NO: 123 LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDSCEDSTYTQLWNWVPE CLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRKCRPGFGVARPGTETSDVVCK PCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPE PSTAPSTSFLLPMGPSPPAEGSTGDLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQE GPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALG CYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKAR SWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSE IPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETTNFRSF1B/IL9R/cGC-S SEQ ID NO: 124 LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDSCEDSTYTQLWNWVPE CLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRKCRPGFGVARPGTETSDVVCK PCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPE PSTAPSTSFLLPMGPSPPAEGSTGDLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQE GPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALG CYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKAR SWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPP KGGALGEGPGASPCNQHSPYWAPPCYTLKPETTNFRSF1/IL9R/cGC-F SEQ ID NO: 125 LVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTYLYNDCPGPGQDTDCRECESGSFTASENHLRHC LSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRHYWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCH AGFFLRENECVSCSNCKKSLECTKLCLPQIENVKGTEDSGTTLIPPWGWPGNTLVAVSIFLLLTGPTYLL FKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLT CGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSR SSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGL HEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGL AESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TNFRSF1/IL9R/cGC-S SEQ ID NO: 126LVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHK GTYLYNDCPGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRH YWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLRENECVSCSNCKKSLECTKLCLPQIENVKG TEDSGTTLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQT WMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPA GCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSG PIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPER TMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHS PYWAPPCYTLKPET BMPR1B/IL9R/CGC-FSEQ ID NO: 127 KKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTSGCLGLEGSDFQCRD TPIPHQRRSIECCTERNECNKDLHPTLPPLKNRDFVDGPIHHRLIPPWGWPGNTLVAVSIFLLLTGPTYL LFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALL TCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGS RSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPG LHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKG LAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET BMPR1B/IL9R/cGC-S SEQ ID NO: 128KKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICS TDGYCFTMIEEDDSGLPVVTSGCLGLEGSDFQCRDTPIPHQRRSIECCTERNECNKDLHPTLPPLKNRDF VDGPIHHRLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQ TWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLP AGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS GPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPE RTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQH SPYWAPPCYTLKPET BMPR1A/IL9R/cGC-FSEQ ID NO: 129 QNLDSMLHGTGMKSDSDQKKSENGVTLAPEDTLPFLKCYCSGHCPDDAINNTCITNGHCFAIIEEDDQGE TTLASGCMKYEGSDFQCKDSPKAQLRRTIECCRTNLCNQYLQPTLPPVVIGPFFDGSIRLIPPWGWPGNT LVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGT PQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDW APTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLET QQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLV TEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET BMPR1A/IL9R/cGC-S SEQ ID NO: 130QNLDSMLHGTGMKSDSDQKKSENGVTLAPEDTLPF LKCYCSGHCPDDAINNTCITNGHCFAIIEEDDQGETTLASGCMKYEGSDFQCKDSPKAQLRRTIECCRTN LCNQYLQPTLPPVVIGPFFDGSIRLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSP AMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEG PGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPOEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGC YGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARS WTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPK GGALGEGPGASPCNQHSPYWAPPCYTLKPETBMPR2/IL9R/CGC-F SEQ ID NO: 131 SQNQERLCAFKDPYQQDLGIGESRISHENGTILCSKGSTCYGLWEKSKGDINLVKQGCWSHIGDPQECHY EECVVTTTPPSIQNGTYRFCCCSTDLCNVNFTENFPPPDTTPLSPPHSFNRDETLIPPWGWPGNTLVAVS IFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGAL EPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSL TRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVA WVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHG NFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET BMPR2/IL9R/cGC-S SEQ ID NO: 132SQNQERLCAFKDPYQQDLGIGESRISHENGTILCS KGSTCYGLWEKSKGDINLVKQGCWSHIGDPQECHYEECVVTTTPPSIQNGTYRFCCCSTDLCNVNFTENF PPPDTTPLSPPHSFNRDETLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQ PLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRL PGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWH LSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQP QPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALG EGPGASPCNQHSPYWAPPCYTLKPETCSF3R/IL9R/cGC-F SEQ ID NO: 133 ECGHISVSAPIVHLGDPITASCIIKQNCSHLDPEPQILWRLGAELQPGGRQQRLSDGTQESIITLPHLNH TQAFLSCCLNWGNSLQILDQVELRAGYPPAIPHNLSCLMNLTTSSLICQWEPGPETHLPTSFTLKSFKSR GNCQTQGDSILDCVPKDGQSHCCIPRKHLLLYQNMGIWVQAENALGTSMSPQLCLDPMDVVKLEPPMLRT MDPSPEAAPPQAGCLQLCWEPWQPGLHINQKCELRHKPQRGEASWALVGPLPLEALQYELCGLLPATAYT LQIRCIRWPLPGHWSDWSPSLELRTTERAPTVRLDTWWRQRQLDPRTVQLFWKPVPLEEDSGRIQGYVVS WRPSGQAGAILPLCNTTELSCTFHLPSEAQEVALVAYNSAGTSRPTPVVFSESRGPALTRLHAMARDPHS LWVGWEPPNPWPQGYVIEWGLGPPSASNSNKTWRMEQNGRATGFLLKENIRPFQLYEIIVTPLYQDTMGP SQHVYAYSQEMAPSHAPELHLKHIGKTWAQLEWVPEPPELGKSPLTHYTIFWTNAQNQSFSAILNASSRG FVLHGLEPASLYHIHLMAASQAGATNSTVLTLMTLTPEGSELHLIPPWGWPGNTLVAVSIFLLLTGPTYL LFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALL TCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGS RSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPG LHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKG LAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET CSF3R/IL9R/cGC-S SEQ ID NO: 134ECGHISVSAPIVHLGDPITASCIIKQNCSHLDPEP QILWRLGAELQPGGRQQRLSDGTQESIITLPHLNHTQAFLSCCLNWGNSLQILDQVELRAGYPPAIPHNL SCLMNLTTSSLICQWEPGPETHLPTSFTLKSFKSRGNCQTQGDSILDCVPKDGQSHCCIPRKHLLLYQNM GIWVQAENALGTSMSPQLCLDPMDVVKLEPPMLRTMDPSPEAAPPQAGCLQLCWEPWQPGLHINQKCELR HKPQRGEASWALVGPLPLEALQYELCGLLPATAYTLQIRCIRWPLPGHWSDWSPSLELRTTERAPTVRLD TWWRQRQLDPRTVQLFWKPVPLEEDSGRIQGYVVSWRPSGQAGAILPLCNTTELSCTFHLPSEAQEVALV AYNSAGTSRPTPVVFSESRGPALTRLHAMARDPHSLWVGWEPPNPWPQGYVIEWGLGPPSASNSNKTWRM EQNGRATGFLLKENIRPFQLYEIIVTPLYQDTMGPSQHVYAYSQEMAPSHAPELHLKHIGKTWAQLEWVP EPPELGKSPLTHYTIFWTNAQNQSFSAILNASSRGFVLHGLEPASLYHIHLMAASQAGATNSTVLTLMTL TPEGSELHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQ TWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLP AGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS GPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPE RTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQH SPYWAPPCYTLKPET CSF1R/IL9R/cGC-FSEQ ID NO: 135 IPVIEPSVPELVVKPGATVTLRCVGNGSVEWDGPPSPHWTLYSDGSSSILSTNNATFQNTGTYRCTEPGD PLGGSAAIHLYVKDPARPWNVLAQEVVVFEDQDALLPCLLTDPVLEAGVSLVRVRGRPLMRHTNYSFSPW HGFTIHRAKFIQSQDYQCSALMGGRKVMSISIRLKVQKVIPGPPALTLVPAELVRIRGEAAQIVCSASSV DVNFDVFLQHNNTKLAIPQQSDFHNNRYQKVLTLNLDQVDFQHAGNYSCVASNVQGKHSTSMFFRVVESA YLNLSSEQNLIQEVTVGEGLNLKVMVEAYPGLQGFNWTYLGPFSDHQPEPKLANATTKDTYRHTFTLSLP RLKPSEAGRYSFLARNPGGWRALTFELTLRYPPEVSVIWTFINGSGTLLCAASGYPQPNVTWLQCSGHTD RCDEAQVLQVWDDPYPEVLSQEPFHKVTVQSLLTVETLEHNQTYECRAHNSVGSGSWAFIPISAGAHTHP PDEFLFTPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQ TWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLP AGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS GPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGG GSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPC NQHSPYWAPPCYTLKPET CSF1R/IL9R/cGC-SSEQ ID NO: 136 IPVIEPSVPELVVKPGATVTLRCVGNGSVEWDGPPSPHWTLYSDGSSSILSTNNATFQNTGTYRCTEPGD PLGGSAAIHLYVKDPARPWNVLAQEVVVFEDQDALLPCLLTDPVLEAGVSLVRVRGRPLMRHTNYSFSPW HGFTIHRAKFIQSQDYQCSALMGGRKVMSISIRLKVQKVIPGPPALTLVPAELVRIRGEAAQIVCSASSV DVNFDVFLQHNNTKLAIPQQSDFHNNRYQKVLTLNLDQVDFQHAGNYSCVASNVQGKHSTSMFFRVVESA YLNLSSEQNLIQEVTVGEGLNLKVMVEAYPGLQGFNWTYLGPFSDHQPEPKLANATTKDTYRHTFTLSLP RLKPSEAGRYSFLARNPGGWRALTFELTLRYPPEVSVIWTFINGSGTLLCAASGYPQPNVTWLQCSGHTD RCDEAQVLQVWDDPYPEVLSQEPFHKVTVQSLLTVETLEHNQTYECRAHNSVGSGSWAFIPISAGAHTHP PDEFLFTPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQ TWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLP AGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS GPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPE RTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQH SPYWAPPCYTLKPETVEGF Receptor 1/IL9R/cGC-F SEQ ID NO: 137SKLKDPELSLKGTQHIMQAGQTLHLQCRGEAAHKW SLPEMVSKESERLSITKSACGRNGKQFCSTLTLNTAQANHTGFYSCKYLAVPTSKKKETESAIYIFISDT GRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKE IGLLTCEATVNGHLYKTNYLTHRQTNTIIDVQISTPRPVKLLRGHTLVLNCTATTPLNTRVQMTWSYPDE KNKRASVRRRIDQSNSHANIFYSVLTIDKMQNKDKGLYTCRVRSGPSFKSVNTSVHIYDKAFITVKHRKQ QVLETVAGKRSYRLSMKVKAFPSPEVVWLKDGLPATEKSARYLTRGYSLIIKDVTEEDAGNYTILLSIKQ SNVFKNLTATLIVNVKPQIYEKAVSSFPDPALYPLGSRQILTCTAYGIPQPTIKWFWHPCNHNHSEARCD FCSNNEESFILDADSNMGNRIESITQRMAIIEGKNKMASTLVVADSRISGIYICIASNKVGTVGRNISFY ITDVPNGFHVNLEKMPTEGEDLKLSCTVNKFLYRDVTWILLRTVNNRTMHYSISKQKMAITKEHSITLNL TIMNVSLQDSGTYACRARNVYTGEEILQKKEITIRDQEAPYLLRNLSDHTVAISSSTTLDCHANGVPEPQ ITWFKNNHKIQQEPGIILGPGSSTLFIERVTEEDEGVYHCKATNQKGSVESSAYLTVQGTSDKSNLELIP PWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVL LSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTL AYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLS CDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPT LKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPC YTLKPET VEGF Receptor 1/IL9R/cGC-SSEQ ID NO: 138 SKLKDPELSLKGTQHIMQAGQTLHLQCRGEAAHKWSLPEMVSKESERLSITKSACGRNGKQFCSTLTLNT AQANHTGFYSCKYLAVPTSKKKETESAIYIFISDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNIT VTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVQIST PRPVKLLRGHTLVLNCTATTPLNTRVQMTWSYPDEKNKRASVRRRIDQSNSHANIFYSVLTIDKMQNKDK GLYTCRVRSGPSFKSVNTSVHIYDKAFITVKHRKQQVLETVAGKRSYRLSMKVKAFPSPEVVWLKDGLPA TEKSARYLTRGYSLIIKDVTEEDAGNYTILLSIKQSNVFKNLTATLIVNVKPQIYEKAVSSFPDPALYPL GSRQILTCTAYGIPQPTIKWFWHPCNHNHSEARCDFCSNNEESFILDADSNMGNRIESITQRMAIIEGKN KMASTLVVADSRISGIYICIASNKVGTVGRNISFYITDVPNGFHVNLEKMPTEGEDLKLSCTVNKFLYRD VTWILLRTVNNRTMHYSISKQKMAITKEHSITLNLTIMNVSLQDSGTYACRARNVYTGEEILQKKEITIR DQEAPYLLRNLSDHTVAISSSTTLDCHANGVPEPQITWFKNNHKIQQEPGIILGPGSSTLFIERVTEEDE GVYHCKATNQKGSVESSAYLTVQGTSDKSNLELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRI FYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSV ALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNN NNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLP SVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLC LVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET VEGF Receptor 2/IL9R/cGC-F SEQ ID NO: 139ASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCR GQRDLDWLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSP FIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISY AGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPS SKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGS GMESLVEATVGERVRIPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTNPI SKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAV SVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVIS FHVTRGPEITLQPDMQPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPTPVCKNLDTLWKLNA TMFSNSTNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLTVLERVAPTITGNLENQTTSIGESI EVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFII EGAQEKTNLELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGN FQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDV LPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQ SSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSG GGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGAS PCNQHSPYWAPPCYTLKPETVEGF Receptor 2/IL9R/cGC-S SEQ ID NO: 140ASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCR GQRDLDWLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSP FIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISY AGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPS SKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGS GMESLVEATVGERVRIPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTNPI SKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAV SVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVIS FHVTRGPEITLQPDMQPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPTPVCKNLDTLWKLNA TMFSNSTNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLTVLERVAPTITGNLENQTTSIGESI EVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCOACSVLGCAKVEAFFII EGAQEKTNLELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGN FQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDV LPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQ SSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQ PERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCN QHSPYWAPPCYTLKPETVEGF Receptor 3/IL9R/cGC-S SEQ ID NO: 141YSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEW AWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSY VFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLH DALYLQCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTFDWDYP GKQAERGKWVPERRSQQTHTELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTEVIVHENPFISVEWLK GPILEATAGDELVKLPVKLAAYPPPEFQWYKDGKALSGRHSPHALVLKEVTEASTGTYTLALWNSAAGLR RNISLELVVNVPPQIHEKEASSPSIYSRHSRQALTCTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQ QDLMPQCRDWRAVTTQDAVNPIESLDTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKVGQDERLIYF YVTTIPDGFTIESKPSEELLEGQPVLLSCQADSYKYEHLRWYRLNLSTLHDAHGNPLLLDCKNVHLFATP LAASLEEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRSHDKHCHKKYLSVQALEAPRLTQNLTDLLV NVSDSLEMQCLVAGAHAPSIVWYKDERLLEEKSGVDLADSNQKLSIQRVREEDAGRYLCSVCNAKGCVNS SASVAVEGSEDKGSMELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLY SVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGN LSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSA LPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQ PQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGP GASPCNQHSPYWAPPCYTLKPETVEGF Receptor 3/IL9R/cGC-F SEQ ID NO: 142YSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEW AWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSY VFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLH DALYLQCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTFDWDYP GKQAERGKWVPERRSQQTHTELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTEVIVHENPFISVEWLK GPILEATAGDELVKLPVKLAAYPPPEFQWYKDGKALSGRHSPHALVLKEVTEASTGTYTLALWNSAAGLR RNISLELVVNVPPQIHEKEASSPSIYSRHSRQALTCTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQ QDLMPQCRDWRAVTTQDAVNPIESLDTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKVGQDERLIYF YVTTIPDGFTIESKPSEELLEGQPVLLSCQADSYKYEHLRWYRLNLSTLHDAHGNPLLLDCKNVHLFATP LAASLEEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRSHDKHCHKKYLSVQALEAPRLTQNLTDLLV NVSDSLEMQCLVAGAHAPSIVWYKDERLLEEKSGVDLADSNQKLSIQRVREEDAGRYLCSVCNAKGCVNS SASVAVEGSEDKGSMELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLY SVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGN LSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSA LPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGS GGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALG EGPGASPCNQHSPYWAPPCYTLKPETActivin R1A ectodomain/IL9R/cGC-F SEQ ID NO: 143MEDEKPKVNPKLYMCVCEGLSCGNEDHCEGQQCFS SLSINDGFHVYQKGCFQVYEQGKMTCKTPPSPGQAVECCQGDWCNRNITAQLPTKGKSFPGTQNFHLELI PPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGV LLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQT LAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGL SCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIP TLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPP CYTLKPETActivin R1A ectodomain/IL9R/cGC-S SEQ ID NO: 144MEDEKPKVNPKLYMCVCEGLSCGNEDHCEGQQCFS SLSINDGFHVYQKGCFQVYEQGKMTCKTPPSPGQAVECCQGDWCNRNITAQLPTKGKSFPGTQNFHLELI PPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGV LLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQT LAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGL SCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLK NLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYT LKPETActivin R1B ectodomain/IL9R/cGC-F SEQ ID NO: 145SGPRGVQALLCACTSCLQANYTCETDGACMVSIFN LDGMEHHVRTCIPKVELVPAGKPFYCLSSEDLRNTHCCYTDYCNRIDLRVPSGHLKEPEHPSMWGPVELI PPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGV LLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQT LAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGL SCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIP TLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPP CYTLKPETActivin R1B ectodomain/IL9R/cGC-S SEQ ID NO: 146SGPRGVQALLCACTSCLQANYTCETDGACMVSIFN LDGMEHHVRTCIPKVELVPAGKPFYCLSSEDLRNTHCCYTDYCNRIDLRVPSGHLKEPEHPSMWGPVELI PPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGV LLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQT LAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGL SCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLK NLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYT LKPETActivin R1C ectodomain/IL9R/cGC-F SEQ ID NO: 147LSPGLKCVCLLCDSSNFTCQTEGACWASVMLTNGK EQVIKSCVSLPELNAQVFCHSSNNVTKTECCFTDFCNNITLHLPTASPNAPKLGPMELIPPWGWPGNTLV AVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQ GALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAP TSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQ GVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTE YHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET Activin RIC ectodomain/IL9R/cGC-SSEQ ID NO: 148 LSPGLKCVCLLCDSSNFTCQTEGACWASVMLTNGKEQVIKSCVSLPELNAQVFCHSSNNVTKTECCFTDF CNNITLHLPTASPNAPKLGPMELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAM FFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPG TRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYG GWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWT FQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGG ALGEGPGASPCNQHSPYWAPPCYTLKPETActivin R2B ectodomain/IL9R/cGC-F SEQ ID NO: 149SGRGEAETRECIYYNANWELERTNQSGLERCEGEQ DKRLHCYASWRNSSGTIELVKKGCWLDDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPE VTYEPPPTAPTLLTLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSV HNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLS SEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALP GNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGG GGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEG PGASPCNQHSPYWAPPCYTLKPETActivin R2B ectodomain/IL9R/cGC-S SEQ ID NO: 150SGRGEAETRECIYYNANWELERTNQSGLERCEGEQ DKRLHCYASWRNSSGTIELVKKGCWLDDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPE VTYEPPPTAPTLLTLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSV HNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLS SEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALP GNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQ PQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGA SPCNQHSPYWAPPCYTLKPETActivin R2A ectodomain/IL9R/cGC-F SEQ ID NO: 151AILGRSETQECLFFNANWEKDRTNQTGVEPCYGDK DKRRHCFATWKNISGSIEIVKQGCWLDDINCYDRTDCVEKKDSPEVYFCCCEGNMCNEKFSYFPEMEVTQ PTSNPVTPKPPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNG NFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSED VLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNT QSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGS GGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGA SPCNQHSPYWAPPCYTLKPETActivin R2A ectodomain/IL9R/cGC-S SEQ ID NO: 152AILGRSETQECLFFNANWEKDRTNQTGVEPCYGDK DKRRHCFATWKNISGSIEIVKQGCWLDDINCYDRTDCVEKKDSPEVYFCCCEGNMCNEKFSYFPEMEVTQ PTSNPVTPKPPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNG NFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSED VLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNT QSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQP QPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPC NQHSPYWAPPCYTLKPETIL10R-alpha/IL9R/cGC-F SEQ ID NO: 153HGTELPSPPSVWFEAEFFHHILHWTPIPNQSESTC YEVALLRYGIESWNSISNCSQTLSYDLTAVTLDLYHSNGYRARVRAVDGSRHSNWTVTNTRFSVDEVTLT VGSVNLEIHNGFILGKIQLPRPKMAPANDTYESIFSHFREYEIAIRKVPGNFTFTHKKVKHENFSLLTSG EVGEFCVQVKPSVASRSNKGMWSKEECISLTRQYFTVTNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKL SPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGP ARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSS SSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHED LQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAES LQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET IL10R-alpha/IL9R/cGC-S SEQ ID NO: 154HGTELPSPPSVWFEAEFFHHILHWTPIPNQSESTC YEVALLRYGIESWNSISNCSQTLSYDLTAVTLDLYHSNGYRARVRAVDGSRHSNWTVTNTRFSVDEVTLT VGSVNLEIHNGFILGKIQLPRPKMAPANDTYESIFSHFREYEIAIRKVPGNFTFTHKKVKHENFSLLTSG EVGEFCVQVKPSVASRSNKGMWSKEECISLTRQYFTVTNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKL SPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGP ARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSS SSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHED LQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQP DYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TGFBR2 ectodomain/IL9R/cGC-F SEQ ID NO: 155TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVR FSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKK KPGETFFMCSCSSDECNDNHFSEEYNTSNPDLLLVIFQLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLS PRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPA RPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSS SSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDL QGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESL QPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TGFBR2 ectodomain/IL9R/cGC-S SEQ ID NO: 156TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVR FSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKK KPGETFFMCSCSSDECNDNHFSEEYNTSNPDLLLVIFQLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLS PRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPA RPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSS SSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDL QGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPD YSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TGFBR1 ectodomain/IL9R/cGC-F SEQ ID NO: 157LQCFCHLCTKDNFTCVTDGLCFVSVTETTDKVIHN SMCIAEIDLIPRDRPFVCAPSSKTGSVTTTYCCNQDHCNKIELPTTVKSSPGLGPVELLIPPWGWPGNTL VAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTP QGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQ QGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVT EYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TGFBR1 ectodomain/IL9R/cGC-SSEQ ID NO: 158 LQCFCHLCTKDNFTCVTDGLCFVSVTETTDKVIHNSMCIAEIDLIPRDRPFVCAPSSKTGSVTTTYCCNQ DHCNKIELPTTVKSSPGLGPVELLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPA MFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGP GTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCY GGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSW TFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKG GALGEGPGASPCNQHSPYWAPPCYTLKPETTIGIT/IL9R/cGC-F SEQ ID NO: 159 MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSFKDRVAPGPGL GLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIPLIPPWGWPGNTLVAVSIFLL LTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCV QEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPA PPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLA GHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSA WSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TIGIT/IL9R/cGC-S SEQ ID NO: 160MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQ VNWEQQDQLLAICNADLGWHISPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEV LESSVAEHGARFQIPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYS VHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNL SSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSAL PGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQP QPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPG ASPCNQHSPYWAPPCYTLKPETFCGR2B/IL9R/cGC-F SEQ ID NO: 161 TPAAPPKAVLKLEPQWINVLQEDSVTLTCRGTHSPESDSIQWFHNGNLIPTHTQPSYRFKANNNDSGEYT CQTGQTSLSDPVHLTVLSEWLVLQTPHLEFQEGETIVLRCHSWKDKPLVKVTFFQNGKSKKFSRSDPNFS IPQANHSHSGDYHCTGNIGYTLYSSKPVTITVQAPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRV KRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPW KSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSS SNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGM LLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPD YSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET FCGR2B/IL9R/cGC-S SEQ ID NO: 162TPAAPPKAVLKLEPQWINVLQEDSVTLTCRGTHSP ESDSIQWFHNGNLIPTHTQPSYRFKANNNDSGEYTCQTGQTSLSDPVHLTVLSEWLVLQTPHLEFQEGET IVLRCHSWKDKPLVKVTFFQNGKSKKFSRSDPNFSIPQANHSHSGDYHCTGNIGYTLYSSKPVTITVQAP LIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGA GVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRV QTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALAC GLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPT LKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPC YTLKPET FCGR1/IL9R/cGC-FSEQ ID NO: 163 QVDTTKAVITLQPPWVSVFQEETVTLHCEVLHLPGSSSTQWFLNGTATQTSTPSYRITSASVNDSGEYRC QRGLSGRSDPIQLEIHRGWLLLQVSSRVFTEGEPLALRCHAWKDKLVYNVLYYRNGKAFKFFHWNSNLTI LKTNISHNGTYHCSGMGKHRYTSAGISVTVKELFPAPVLNASVTSPLLEGNLVTLSCETKLLLQRPGLQL YFSFYMGSKTLRGRNTSSEYQILTARREDSGLYWCEAATEDGNVLKRSPELELQVLGLQLPTPVWFHLIP PWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVL LSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTL AYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLS CDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPT LKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPC YTLKPET FCGR1/IL9R/cGC-SSEQ ID NO: 164 QVDTTKAVITLQPPWVSVFQEETVTLHCEVLHLPGSSSTQWFLNGTATQTSTPSYRITSASVNDSGEYRC QRGLSGRSDPIQLEIHRGWLLLQVSSRVFTEGEPLALRCHAWKDKLVYNVLYYRNGKAFKFFHWNSNLTI LKTNISHNGTYHCSGMGKHRYTSAGISVTVKELFPAPVLNASVTSPLLEGNLVTLSCETKLLLQRPGLQL YFSFYMGSKTLRGRNTSSEYQILTARREDSGLYWCEAATEDGTNVLKRSPELELQVLGLQLPTPVWFHLI PPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGV LLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQT LAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGL SCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLK NLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYT LKPET 2B4/IL9R/cCG-F SEQ ID NO: 165CQGSADHVVSISGVPLQLQPNSIQTKVDSIAWKKL LPSQNGFHHILKWENGSLPSNTSNDRFSFIVKNLSLLIKAAQQQDSGLYCLEVTSISGKVQTATFQVFVF ESLLPDKVEKPRLQGQGKILDRGRCQVALSCLVSRDGNVSYAWYRGSKLIQTAGNLTYLDEEVDINGTHT YTCNVSNPVSWESHTLNLTQDCQNAHQEFRFWPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKR IFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKS VALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSN NNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLL PSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYS ERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET 2B4/IL9R/cCG-S SEQ ID NO: 166CQGSADHVVSISGVPLQLQPNSIQTKVDSIAWKKL LPSQNGFHHILKWENGSLPSNTSNDRFSFIVKNLSLLIKAAQQQDSGLYCLEVTSISGKVQTATFQVFVF ESLLPDKVEKPRLQGQGKILDRGRCQVALSCLVSRDGNVSYAWYRGSKLIQTAGNLTYLDEEVDINGTHT YTCNVSNPVSWESHTLNLTQDCQNAHQEFRFWPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKR IFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKS VALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSN NNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLL PSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERL CLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET LAIR1/IL9R/cGC-F SEQ ID NO: 167QEEDLPRPSISAEPGTVIPLGSHVTFVCRGPVGVQ TFRLERESRSTYNDTEDVSQASPSESEARFRIDSVSEGNAGPYRCIYYKPPKWSEQSDYLELLVKETSGG PDSPDTEPGSSAGPTQRPSDNSHNEHAPASQGLKAEHLYLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKL SPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGP ARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSS SSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHED LQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAES LQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET LAIR1/IL9R/cGC-S SEQ ID NO: 168QEEDLPRPSISAEPGTVIPLGSHVTFVCRGPVGVQ TFRLERESRSTYNDTEDVSQASPSESEARFRIDSVSEGNAGPYRCIYYKPPKWSEQSDYLELLVKETSGG PDSPDTEPGSSAGPTQRPSDNSHNEHAPASQGLKAEHLYLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKL SPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGP ARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSS SSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHED LQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQP DYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET CD5/IL-9R/cGC-F SEQ ID NO: 169RLSWYDPDFQARLTRSNSKCQGQLEVYLKDGWHMV CSQSWGRSSKQWEDPSQASKVCQRLNCGVPLSLGPFLVTYTPQSSIICYGQLGSFSNCSHSRNDMCHSLG LTCLEPQKTTPPTTRPPPTTTPEPTAPPRLQLVAQSGGQHCAGVVEFYSGSLGGTISYEAQDKTQDLENF LCNNLQCGSFLKHLPETEAGRAQDPGEPREHQPLPIQWKIQNSSCTSLEHCFRKIKPQKSGRVLALLCSG FQPKVQSRLVGGSSICEGTVEVRQGAQWAALCDSSSARSSLRWEEVCREQQCGSVNSYRVLDAGDPTSRG LFCPHQKLSQCHELWERNSYCKKVFVTCQDPNPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKR IFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKS VALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSN NNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLL PSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYS ERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET CD5/IL-9R/cGC-S SEQ ID NO: 170RLSWYDPDFQARLTRSNSKCQGQLEVYLKDGWHMV CSQSWGRSSKQWEDPSQASKVCQRLNCGVPLSLGPFLVTYTPQSSIICYGQLGSFSNCSHSRNDMCHSLG LTCLEPQKTTPPTTRPPPTTTPEPTAPPRLQLVAQSGGQHCAGVVEFYSGSLGGTISYEAQDKTQDLENF LCNNLQCGSFLKHLPETEAGRAQDPGEPREHQPLPIQWKIQNSSCTSLEHCFRKIKPQKSGRVLALLCSG FQPKVQSRLVGGSSICEGTVEVRQGAQWAALCDSSSARSSLRWEEVCREQQCGSVNSYRVLDAGDPTSRG LFCPHQKLSQCHELWERNSYCKKVFVTCQDPNPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKR IFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKS VALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSN NNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLL PSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERL CLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TWEAKR/IL9R/cGC-F SEQ ID NO: 171EQAPGTAPCSRGSSWSADLDKCMDCASCRARPHSD FCLGCAAAPPAPFRLLWPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQP LYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLP GNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHL SALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGG GSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGA LGEGPGASPCNQHSPYWAPPCYTLKPETTWEAKR/IL9R/cGC-S SEQ ID NO: 172 EQAPGTAPCSRGSSWSADLDKCMDCASCRARPHSDFCLGCAAAPPAPFRLLWPLIPPWGWPGNTLVAVSI FLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALE PCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLT RPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAW VLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSA WSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TWEAKR/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 173EQAPGTAPCSRGSSWSADLDKCMDCASCRARPHSD FCLGCAAAPPAPFRLLWPVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQT WMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPA GCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSG PIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGG SERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCN QHSPYWAPPCYTLKPETTWEAKR/IL9R/cGC-S/TNFR1-TM SEQ ID NO: 174EQAPGTAPCSRGSSWSADLDKCMDCASCRARPHSD FCLGCAAAPPAPFRLLWPVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQT WMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPA GCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSG PIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPER TMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHS PYWAPPCYTLKPETOPG/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 175ETFPPKYLHYDEETSHQLLCDKCPPGTYLKQHCTA KWKTVCAPCPDHYYTDSWHTSDECLYCSPVCKELQYVKQECNRTHNRVCECKEGRYLEIEFCLKHRSCPP GFGVVQAGTPERNTVCKRCPDGFFSNETSSKAPCRKHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCG IDVTLCEEAFFRFAVPTKFTPNWLSVLVDNLPGTKVNAESVERIKRQHSSQEQTFQLLKLWKHQNKDQDI VKKIIQDIDLCENSVQRHIGHANLTFEQLRSLMESLPGKKVGAEDIEKTIKACKPSDQILKLLSLWRIKN GDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRFLHSFTMYKLYQKLFLEMIGNQVQSVKISCLVLLPL VIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGAL EPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSL TRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVA WVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHG NFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET OPG/IL9R/CGC-S/TNFR1-TM SEQ ID NO: 176ETFPPKYLHYDEETSHQLLCDKCPPGTYLKQHCTA KWKTVCAPCPDHYYTDSWHTSDECLYCSPVCKELQYVKQECNRTHNRVCECKEGRYLEIEFCLKHRSCPP GFGVVQAGTPERNTVCKRCPDGFFSNETSSKAPCRKHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCG IDVTLCEEAFFRFAVPTKFTPNWLSVLVDNLPGTKVNAESVERIKRQHSSQEQTFQLLKLWKHQNKDQDI VKKIIQDIDLCENSVQRHIGHANLTFEQLRSLMESLPGKKVGAEDIEKTIKACKPSDQILKLLSLWRIKN GDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRFLHSFTMYKLYQKLFLEMIGNQVQSVKISCLVLLPL VIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGAL EPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSL TRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVA WVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFS AWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TACI/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 177MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCP EEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQ HPKQCAYFCENKLRSPVNLPPELRRQRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKLSADQVALVYS VLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGT PQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDW APTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLET QQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLV TEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TACI/IL9R/cGC-S/TNFR1-TMSEQ ID NO: 178 MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLS CRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRRQRSGEVENNSDNSGRYQGLE HRGSEASPALPGLKLSADQVALVYSVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSV HNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLS SEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALP GNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQ PQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGA SPCNQHSPYWAPPCYTLKPETBCMA/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 179MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPL TCQRYCNASVTNSVKGTNAVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQ TWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLP AGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS GPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGG GSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPC NQHSPYWAPPCYTLKPETBCMA/IL9R/cGC-S/TNFR1-TM SEQ ID NO: 180MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLT CQRYCNASVTNSVKGTNAVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQT WMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPA GCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSG PIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPER TMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHS PYWAPPCYTLKPETNGFR/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 181KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTV CEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSG LVFSCQDKQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRSTPPE GSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDNVLLPLVIFFGLCLLSLLFIGLMY VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARP WKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSS SSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQG MLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQP DYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET NGFR/IL9R/cGC-S/TNFR1-TM SEQ ID NO: 182KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTV CEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSG LVFSCQDKQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRSTPPE GSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDNVLLPLVIFFGLCLLSLLFIGLMY VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARP WKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSS SSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQG MLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYS ERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET EDAR/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 183EYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCG YGTKDEDYGCVPCPAEKFSKGGYQICRRHKDCEGFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIY GMVCYSCLLAPPNTKECVGATSGASANFPGTSGSSTLSPFQHAHKELSGQGHLATAVLLPLVIFFGLCLL SLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATA LLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSE GSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQR PGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVS KGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET EDAR/IL9R/cGC-S/TNFR1-TM SEQ ID NO: 184EYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCG YGTKDEDYGCVPCPAEKFSKGGYQICRRHKDCEGFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIY GMVCYSCLLAPPNTKECVGATSGASANFPGTSGSSTLSPFQHAHKELSGQGHLATAVLLPLVIFFGLCLL SLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATA LLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSE GSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQR PGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGL AESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DCR2 (TNFRSF10D)/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 185ATIPRQDEVPQQTVAPQQQRRSLKEEECPAGSHRS EYTGACNPCTEGVDYTIASNNLPSCLLCTVCKSGQTNKSSCTTTRDTVCQCEKGSFQDKNSPEMCRTCRT GCPRGMVKVSNCTPRSDIKCKNESAASSTGKTPAAEETVTTILGMLASPYHVLLPLVIFFGLCLLSLLFI GLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCG PARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSS SSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHE DLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAE SLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DCR2 (TNFRSF10D)/IL9R/cGC-S/TNFR1-TM SEQ ID NO: 186ATIPRQDEVPQQTVAPQQQRRSLKEEECPAGSHRS EYTGACNPCTEGVDYTIASNNLPSCLLCTVCKSGQTNKSSCTTTRDTVCQCEKGSFQDKNSPEMCRTCRT GCPRGMVKVSNCTPRSDIKCKNESAASSTGKTPAAEETVTTILGMLASPYHVLLPLVIFFGLCLLSLLFI GLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCG PARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSS SSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHE DLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQ PDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DCR1 (TNFRSF10C)/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 187ATTARQEEVPQQTVAPQQQRHSFKGEECPAGSHRS EHTGACNPCTEGVDYTNASNNEPSCFPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCSR CPSGEVQVSNCTSWDDIQCVEEFGANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTT SPGTPAPAAEETMTTSPGTPAPAAEETMITSPGTPAVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQE GPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALG CYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKAR SWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSE IPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETDCR1 (TNFRSF10C)/IL9R/cGC-S/TNFR1-TM SEQ ID NO: 188ATTARQEEVPQQTVAPQQQRHSFKGEECPAGSHRS EHTGACNPCTEGVDYTNASNNEPSCFPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCSR CPSGEVQVSNCTSWDDIQCVEEFGANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTT SPGTPAPAAEETMTTSPGTPAPAAEETMITSPGTPAVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQE GPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALG CYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKAR SWTFOPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPP KGGALGEGPGASPCNQHSPYWAPPCYTLKPETCD40/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 189EPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFT ETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSC SPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRVL LPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQ GALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAP TSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQ GVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTE YHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET CD40/IL9R/cGC-S/TNFR1-TM SEQ ID NO: 190EPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFT ETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSC SPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRVL LPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQ GALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAP TSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQ GVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPOPQPERTMPRIPTLKNLEDLVTEYHG NFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET FAS/IL9 R/cGC-F/TN FR1-TM SEQ ID NO: 191QVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCH KPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCK PNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKEEGSRSNVLLPLVIFFGLCLLSLLFIGLMYVKRI FYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSV ALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNN NNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLP SVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSE RLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET FAS/IL9R/cGC-S/TN FR1-TM SEQ ID NO: 192QVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCH KPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCK PNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKEEGSRSNVLLPLVIFFGLCLLSLLFIGLMYVKRI FYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSV ALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNN NNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLP SVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLC LVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DR4/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 193ASGTEAAAATPSKVWGSSAGRIEPRGGGRGALPTS MGQHGPSARARAGRAPGPRPAREASPRLRVHKTFKFVVVGVLLQVVPSSAATIKLHDQSIGTQQWEHSPL GELCPPGSHRSEHPGACNRCTEGVGYTNASNNLFACLPCTACKSDEEERSPCTTTRNTACQCKPGTFRND NSAEMCRKCSRGCPRGMVKVKDCTPWSDIECVHKESGNGHNVLLPLVIFFGLCLLSLLFIGLMYVKRIFY QNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVAL EEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNN YCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSV LSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERL CLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DR4/IL9R/cGC-S/TNFR1-TM SEQ ID NO: 194ASGTEAAAATPSKVWGSSAGRIEPRGGGRGALPTS MGQHGPSARARAGRAPGPRPAREASPRLRVHKTFKFVVVGVLLQVVPSSAATIKLHDQSIGTQQWEHSPL GELCPPGSHRSEHPGACNRCTEGVGYTNASNNLFACLPCTACKSDEEERSPCTTTRNTACQCKPGTFRND NSAEMCRKCSRGCPRGMVKVKDCTPWSDIECVHKESGNGHNVLLPLVIFFGLCLLSLLFIGLMYVKRIFY QNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVAL EEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNN YCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSV LSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLV SEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DR6/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 194QPEQKASNLIGTYRHVDRATGQVLTCDKCPAGTYV SEHCTNTSLRVCSSCPVGTFTRHENGIEKCHDCSQPCPWPMIEKLPCAALTDRECTCPPGMFQSNATCAP HTVCPVGWGVRKKGTETEDVRCKQCARGTFSDVPSSVMKCKAYTDCLSQNLVVIKPGTKETDNVCGTLPS FSSSTSPSPGTAIFPRPEHMETHEVPSSTYVPKGMNSTESNSSASVRPKVLSSIQEGTVPDNTSSARGKE DVNKTLPNLQVVNHQQGPHHRHILKLLPSMEATGGEKSSTPIKGPKRGHPRQNLHKHFDINEHVLLPLVI FFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEP CVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTR PAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWV LAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNF SAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DR6/IL9R/cGC-S/TNFR1-TM SEQ ID NO: 195QPEQKASNLIGTYRHVDRATGQVLTCDKCPAGTYV SEHCTNTSLRVCSSCPVGTFTRHENGIEKCHDCSQPCPWPMIEKLPCAALTDRECTCPPGMFQSNATCAP HTVCPVGWGVRKKGTETEDVRCKQCARGTFSDVPSSVMKCKAYTDCLSQNLVVIKPGTKETDNVCGTLPS FSSSTSPSPGTAIFPRPEHMETHEVPSSTYVPKGMNSTESNSSASVRPKVLSSIQEGTVPDNTSSARGKE DVNKTLPNLQVVNHQQGPHHRHILKLLPSMEATGGEKSSTPIKGPKRGHPRQNLHKHFDINEHVLLPLVI FFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEP CVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTR PAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWV LAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAW SGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DR5/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 196ITQQDLAPQQRAAPQQKRSSPSEGLCPPGHHISED GRDCISCKYGQDYSTHWNDLLFCLRCTRCDSGEVELSPCTTTRNTVCQCEEGTFREEDSPEMCRKCRTGC PRGMVKVGDCTPWSDIECVHKESGTKHSGEVPAVEETVTSSPGTPASPCSV LLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTP QGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQ QGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVT EYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DR5/IL9R/cGC-S/TNFR1-TM SEQ ID NO: 197ITQQDLAPQQRAAPQQKRSSPSEGLCPPGHHISED GRDCISCKYGQDYSTHWNDLLFCLRCTRCDSGEVELSPCTTTRNTVCQCEEGTFREEDSPEMCRKCRTGC PRGMVKVGDCTPWSDIECVHKESGTKHSGEVPAVEETVTSSPGTPASPCSV LLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTP QGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQ QGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYH GNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DR3/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 198QGGTRSPRCDCAGDFHKKIGLFCCRGCPAGHYLKA PCTEPCGNSTCLVCPQDTFLAWENHHNSECARCQACDEQASQVALENCSAVADTRCGCKPGWFVECQVSQ CVSSSPFYCQPCLDCGALHRHTRLLCSRRDTDCGTCLPGFYEHGDGCVSCPTSTLGSCPERCAAVCGWRQ VLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGT PQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDW APTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLET QQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLV TEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET DR3/IL9R/cGC-S/TNFR1-TMSEQ ID NO: 199 QGGTRSPRCDCAGDFHKKIGLFCCRGCPAGHYLKAPCTEPCGNSTCLVCPQDTFLAWENHHNSECARCQA CDEQASQVALENCSAVADTRCGCKPGWFVECQVSQCVSSSPFYCQPCLDCGALHRHTRLLCSRRDTDCGT CLPGFYEHGDGCVSCPTSTLGSCPERCAAVCGWRQVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSP AMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEG PGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGC YGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARS WTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPK GGALGEGPGASPCNQHSPYWAPPCYTLKPETTNFRSFlB/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 200LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKC SPGQHAKVFCTKTSDTVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCA LSKQEGCRLCAPLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMD AVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDVLLPLVIFFG LCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQ EATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAP PDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAG HCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAW SGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TNFRSFlB/IL9R/cGC-S/TNFR1-TM SEQ ID NO: 201LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKC SPGQHAKVFCTKTSDTVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCA LSKQEGCRLCAPLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMD AVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDVLLPLVIFFG LCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQ EATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAP PDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAG HCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGV SKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET TNFRSF1/IL9R/cGC-F/TNFR1-TM SEQ ID NO: 202LVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHK GTYLYNDCPGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRH YWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLRENECVSCSNCKKSLECTKLCLPQIENVKG TEDSGTTVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLL SQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLA YLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSC DHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTL KNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCY TLKPET TNFRSF1/IL9R/cGC-S/TNFR1-TMSEQ ID NO: 203 LVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTYLYNDCPGPGQDTDCRECESGSFTASENHLRHC LSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRHYWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCH AGFFLRENECVSCSNCKKSLECTKLCLPQIENVKGTEDSGTTVLLPLVIFFGLCLLSLLFIGLMYVKRIF YQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVA LEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNN NYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPS VLSKARSWTFOPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCL VSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET

What is claimed is:
 1. A recombinant nucleic acid molecule encoding achimeric receptor, said chimeric receptor comprising: an extracellularportion comprising a binding domain of an endogenous cytokine receptor;an intracellular portion comprising an endodomain of an IL-9 receptor;and a transmembrane domain that joins the extracellular portion and theintracellular portion.
 2. The recombinant nucleic acid molecule of claim1 further comprising one or more linkers.
 3. The recombinant nucleicacid molecule of claim 1, wherein the endogenous cytokine receptor isselected from IL-2rb, IL-2ra, IL-4r, IL-7ra, IL-15ra, and IL-21ra. 4.The recombinant nucleic acid molecule according to claim 1, wherein theendogenous cytokine receptor comprises an amino acid sequence having atleast 80% sequence identity to an amino acid sequence selected from SEQID Nos: 1-6.
 5. The recombinant nucleic acid molecule according to claim1, wherein the transmembrane domain is selected from the transmembranedomain of IL-9, IL-7ra, IL-2rb, and TNFR1.
 6. The recombinant nucleicacid molecule according to claim 5, wherein the transmembrane domaincomprises an amino acid sequence selected from SEQ ID Nos: 53-56.
 7. Therecombinant nucleic acid molecule according to claim 1, wherein therecombinant nucleic acid molecule is incorporated into a vector.
 8. Therecombinant nucleic acid molecule according to claim 1, wherein thechimeric receptor comprises an amino acid sequence having at least 80%sequence identity to an amino acid sequence selected from SEQ ID Nos:63-80.
 9. The recombinant nucleic acid molecule according to claim 1,wherein the chimeric receptor comprises the amino acid sequence selectedfrom SEQ ID Nos. 63 and
 72. 10. The recombinant nucleic acid moleculeaccording to claim 1, further comprising a signal sequence.
 11. Therecombinant nucleic acid molecule according to claim 10, wherein thesignal sequence comprises the amino acid sequence ofMAAPALSWRLPLLILLLPLATSWASA (SEQ ID NO: 62).
 12. The recombinant nucleicacid molecule according to claim 1 further comprising a 2A linker. 13.The recombinant nucleic acid molecule according to claim 1 furthercomprising a nucleic acid sequence encoding a chimeric antigen receptor.14. An expression vector comprising the recombinant nucleic acidmolecule of claim
 1. 15. A recombinant cell comprising the recombinantnucleic acid construct according to claim
 1. 16. The recombinant cell ofclaim 15, wherein the recombinant cell is a eukaryotic cell.
 17. Therecombinant cell of claim 16, wherein the eukaryotic cell is an animalcell.
 18. The recombinant cell of claim 17, wherein the animal cell is amammalian cell.
 19. The recombinant cell of claim 18, wherein themammalian cell is an immune cell, a neuron, an epithelial cell, andendothelial cell, or a stem cell.
 20. The recombinant cell of claim 19,wherein the recombinant cell is an immune cell or a dendritic cell. 21.The recombinant cell of claim 20, wherein the immune cell is a B cell, amonocyte, a natural killer (NK) cell, a basophil, an eosinophil, aneutrophil, a dendritic cell, a macrophage, a regulatory T cell, ahelper T cell (T_(H)), a cytotoxic T cell (T_(CTL)), or other T cell.22. A polypeptide encoded by the recombinant nucleic acid of claim 1.23. The polypeptide of claim 22, wherein the polypeptide comprises anamino acid sequence having at least 80% sequence identity to an aminoacid sequence selected from SEQ ID Nos: 1-6.
 24. The polypeptide ofclaim 22, wherein the polypeptide comprises an amino acid sequenceselected from SEQ ID Nos: 53-56.
 25. The polypeptide of claim 22,wherein the polypeptide comprises an amino acid sequence having at least80% sequence identity to an amino acid sequence selected from SEQ IDNos: 63-80.